Substituted 4,5,6,7-Tetrahydro-1H-Pyrazolo[4,3-C]Pyridines, Their Use as Medicament, and Pharmaceutical Preparations Comprising Them

ABSTRACT

The invention relates to substituted 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridines of formula (I), their use as medicament, and pharmaceutical preparations comprising them. The compounds of formula (I) act on the TASK-1 potassium channel. The compounds are particularly suitable for the treatment or prevention of atrial arrhythmias, for example atrial fibrillation (AF) or atrial flutter.

The invention relates to 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinecompounds of the formula I,

The compounds of formula I act on the TASK-1 (KCNK3) potassium channel.The compounds are suitable for the treatment of several pathologies andparticularly suitable as antiarrhythmic active ingredients, inparticular for the treatment and prophylaxis of atrial arrhythmias, forexample atrial fibrillation (AF) or atrial flutter.

Potassium channels are widespread membrane proteins which, owing totheir influences on cell membrane potentials, play an important role inmany physiological processes. Within the various classes of thepotassium channels, a distinction is drawn on the basis of theirmolecular structure between three large groups which are characterizedby the number of transmembrane domains (2, 4 or 6). The group of thepotassium channels with four transmembrane segments is delimited fromthe two others in that their representatives each have two pore domains,which is why these channels are also referred to as K_(2P) channels(Coetzee W. J. et al; Molecular diversity of K+ channels; Ann. New YorkAcad. Sci. 1999 (868), 233-285). In functional terms, K_(2P) channelsare characterized in that the “leak” or “background” currents flowthrough them, which play an important role for the resting membranepotential and hence the excitability of nerve or muscle cells.

A family which is of particular interest among the K_(2P) channels isthat of the TASK channels (tandem of P domains in a weak inwardlyrectifying K⁺ channel, [TWIK]-related acid-sensitive K⁺ channels), whichinclude TASK-1, TASK-3, and TASK-5 subtype (D. A. Bayliss, P. Barrett,Trends in Pharmacological Sciences, 2008, 29(11), 566-575). Other termsused in the literature for the underlying genes are KCNK3 or K2P3.1(TASK-1), KCNK9 or K2P9.1 (TASK-3) and KCNK15 or K2P15.1 (TASK-5). Thegreatest homology within this family is possessed by the TASK-1 andTASK-3 channels with an amino acid identity of more than 50%.Dimerization of K_(2P) channels forms functional potassium channels witha total of four pore units. The streams which flow through thesechannels are referred to in the literature as IKso stream. In additionto a homodimerization of, for example, two TASK-1 or two TASK-3proteins, heterodimerization of TASK-1 and TASK-3 is also possible inthis context (Berg A. P., Talley E. M., Manger J. P., Bayliss D. A.;Motoneurons express Heteromeric TWIK-related acid-sensitive K+(TASK)Channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits; J.Neuroscience 2004 (24), 6693-6702).

The TASK channels are notable in particular for their very strongdependence upon the extracellular pH in the physiological range (pK ca.6,5-7,5). The channels are inhibited at acidic pH and activated atalkaline pH. Owing to this pH dependence, the physiological function ofa sensor which translates small changes in the extracellular pH tocorresponding cellular signals is ascribed to the TASK channels (DupratF., Lesage F., Fink M., Reyes R., Heurteaux C., Lazdunski M.; TASK, ahuman background K+ channel to sense external pH variations nearphysiological pH; EMBO J. 1997 (16), 5464-5471; Patel A. J., Honore E.;Properties and modulation of mammalian 2P domain K+ channels; TrendsNeurosci. 2001 (24), 339-346).

TASK-1 knock-out mice show a mild phenotype and have been described andappear generally in good health and show normal breeding behaviour(Journal of Neuroscience (2005), 25(49), 11455-11467).

TASK-1 is expressed in the brain and also in spinal ganglia and someperipheral tissues, for example pancreas, placenta, uterus, lung, heart,kidney, small intestine and stomach. In addition, TASK-1 has beendetected in the chemosensitive cells of the brainstem and of the carotidbodies, and also the motor neurons of the hypoglossal nerve (Medhurst A.D., Rennie G., Chapman C. G., Meadows H., Duckworth M. D., Kelsell R.E., Glober I. I., Pangalos M. N.; Distribution analysis of human twopore domain potassium channels in tissues of the central nervous systemand periphery; Mol. Brain Res. 2001 (86), 101-114). Electrical currentswhich are caused by TASK-1 potassium channels have been detected inmotor neurons of the hypoglossal nerve, a motor cranial nerve whichpossesses the most important function for the maintenance and patency ofthe upper respiratory pathways, and locus coeruleus. It has been foundthat TASK-1 channels are involved in respiratory regulation inrespiratory neurons of the brainstem, in carotid bodies and in motorneurons of the hypoglossal nerve, and also in neuroepithelial cells ofthe lung. In the event of inadequate respiration (hypoxia, hinderedbreathing) and in the event of physical stress, either via a rise in theCO₂ concentration and the resulting acidosis or via acidic metabolites,there is a lowering of the pH and hence a blockage of the pH-dependentTASK-1 channels. This depolarizes the cells, which leads to theactivation of the neurons involved in the respiratory regulation(Buckler K. J., Williams B. A., Honore E.; An oxygen-, acid- andanaesthetic-sensitive TASK-like background potassium channel in ratarterial chemoreceptor cells; J. Physiol. 2000 (525), 135-142; BaylissD. A., Talley E. M., Sirois J. E., Lei Q.; TASK-1 is a highly modulatedpH-sensitive ‘leak’ K+ channel expressed in brainstem respiratoryneurons; Respiration Physiology 2001 (129), 159-174).

An increase in the activity of chemosensitive neurons in conjunctionwith an activation of the motor neurons of the hypoglossal nerve throughblockage of the TASK-1 channel can stimulate respiration andsimultaneously stabilize the upper airways to protect them from collapseand occlusion. Moreover, snoring can be inhibited by stabilizing theupper airway via an increase in pharyngeal muscle activity. The blockageof the TASK-1 ion channels is therefore useful in the treatment ofrespiratory disorders, for example of sleep apnea (Brendel, J.;Goegelein, H.; Wirth, K.; Kamm, W., WO 2007/124849).

In cultivated granulosa cells of the cerebellum, it has been shown thatgenetic inactivation of TASK channels brings about neuroprotectiveaction (Lauritzen I., Zanzouri M., Honoré E., Duprat F., Ehrengruber M.U., Lazdunski M., Patel A. J.; K⁺-dependent cerebellar granule neuronapoptosis—Role of Task leak K⁺ channels; J. Biol. Chem. 2003 (278),32068-32076). It has also been shown that TASK-1 channels areresponsible for programmed cell death (apoptosis) in granulosa cells,and that the cell death can be prevented by blocking the TASK-3. Thus,the development of specific inhibitors of the TASK-⅓ channels can beuseful for the treatment of neurodegenerative disorders (Patel A. J.,Lazdunski M., The 2P-domain K⁺ channels: role in apoptosis andtumorigenesis, Pflugers Arch. 2004 (448), 261-273).

It has been stated that TASK-1 is relevant for setting the restingmembrane potential and balancing neuronal excitability that is expressedon T cells and neurons, and is a key modulator of T cell immunity andneurodegeneration in autoimmune central nervous system inflammation.After induction of experimental autoimmune encephalomyelitis, anexperimental model mimicking multiple sclerosis, TASK1(−/−) mice showeda significantly reduced clinical severity and markedly reduced axonaldegeneration compared with wild-type controls. T cells from TASK1(−/−)mice displayed impaired T cell proliferation and cytokine production,while the immune repertoire is otherwise normal. In addition to theseeffects on systemic T cell responses, TASK1 exhibits an independentneuroprotective effect which was demonstrated using both a model ofacutely prepared brain slices cocultured with activated T cells as wellas in vitro cultivation experiments with isolated optic nerves.Preventive blockade of TASK1 significantly ameliorated experimentalautoimmune encephalomyelitis after immunization and significantlyreduced disease severity and was capable of lowering progressive loss ofbrain parenchymal volume as assessed by magnetic resonance imaging. ThusTASK-1 blockers are potent compounds useful for the therapy ofinflammatory and degenerative central nervous system disorders (BittnerStefan; Meuth Sven G; Gobel Kerstin; Melzer Nico; Herrmann Alexander M;Simon Ole J; Weishaupt Andreas; Budde Thomas; Bayliss Douglas A;Bendszus Martin; Wiendl Heinz, Brain: a journal of neurology (2009),132(Pt 9), 2501-16).

TASK-1, a member of two-pore-domain (K2P) potassium channel family, hasemerged as a target for the pharmacological treatment of atrialfibrillation recently.

Two-pore-domain (K2P) potassium channels mediate background potassiumcurrents, stabilizing resting membrane potential and expediting actionpotential repolarization. In the heart, TASK-1 channels have been shownto play a role in cardiac repolarization, (Basic Res Cardiol. 2011January; 106(1):75-87, Putzke C, Wemhöner K, Sachse F B, Rinné S,Schlichthörl G, Li X T, Jaé L, Eckhardt I, Wischmeyer E, Wulf H,Preisig-Müller R, Daut J, Decher N (2007), Cardiovascular Research, 75:59-68).

Atrial fibrillation (AF) and atrial flutter are extremely common cardiacrhythm disorder that causes substantial morbidity and contributes tomortality (Journal of Clinical Invest. 2011; 121 (8):2955-2968).Presently available therapeutic approaches have major limitations,including limited efficacy and potentially serious side effects such asmalignant ventricular arrhythmia induction or negative inotropiceffects. The occurrence of AF increases with age and frequently leads tofatal sequelae such as stroke. The class I and III antiarrhythmics inuse at present reduce the rate of recurrence of AF but are used to onlya limited extent because of their potential proarrhythmic side effectsand limited efficacy. The growing incidence of AF emphasizes theimportance of identifying appropriate treatments, particularly drugs,that are safe, effective, and associated with improved clinicaloutcomes.

It has been shown that in atrial fibrillation and flutter re-entrantmechanism play an important role in the induction and maintenance of thearrhythmia. Such reentries or re-entrant waves occur when the cardiactissue has a low conduction velocity and, at the same time, shortrefractory periods. Increasing the myocardial refractory period byprolonging the action potential is an acknowledged mechanism forterminating arrhythmias or for preventing them to develop (T. J.Colatsky et al., Drug Dev. Res. 19, 1990, 129-140; “Potassium channelsas targets for antiarrhythmic drug action”). The length of the actionpotential is essentially determined by the extent of repolarizing K⁺currents which flow out of the cells through various K⁺ channels. TASK-1constitutes one of those repolarizing potassium currents. Its inhibitionprolong the action potential and thereby refractoriness.

Most of the known class III antiarrhythmics (e.g. dofetilide, E4031 andd-sotalol) block predominantly or exclusively the rapidly activatingpotassium channel IK_(r), which can be detected both in cells of thehuman ventricle and in the atrium. It has emerged that these compoundshave an increased proarrhythmic risk at heart rates which are low ornormal, and arrhythmias referred to as torsades de pointes have beenobserved in particular (D. M. Roden, Am. J. Cardiol. 72, 1993, 44B-49B;“Current status of class III antiarrhythmic drug therapy”). Apart fromthis proarrhythmic risk, the therapeutic efficacy of the I_(Kr) blockershas been found to decline under the conditions of tachycardia(electrical tachycardic atrial remodelling).

TASK-1 expression in the human heart has been shown to be restricted tothe atria with no or very little expression in the ventricles. A furtheradvantage is that TASK-1 expression is not decreased but even slightlyincreased in atrial fibrillation patients compared with sinus rhythmpatients, by contrast a decreased expression of other atrial K⁺ channelshas been reported in atrial fibrillation patients compared with sinusrhythm patients: see for example Basic. Res. Cardiol. 2003, 98, 137-148,JACC Vol. 37, No. 3, 2001). Thus, TASK-1 is still expressed in thetarget patient population (Journal of Molecular Medicine 2004, 308-316;European Journal of Physiology 2005, 450, 201-208, WO 2005/016965;Journal of Thoracic and Cardiovascular Surgery 2005).

In spite of the great physiological significance of the TASK channels,only very few pharmacological modulators of these channels are known todate in the literature.

It has been stated that an activation of the TASK-1 channel can beachieved by therapeutic concentrations of the inhalative anestheticshalothane and isoflurane (Patel A. J., Honoré E., Lesage F., Fink M.,Romey G., Lazdunski M.; Inhalational anesthetics activatetwo-pore-domain background K+ channels; Nature Neurosci. 1999 (2),422-426). Furthermore, some Kv1.5 blockers which also inhibit theTASK-channel are described in the state of the art (Brendel, J.;Goegelein, H.; Wirth, K.; Kamm, W., WO 2007/124849, Brendel, J.;Englert, H. C.; Wirth, K.; Wagner, M.; Ruxer, J.-M.; Pilorge, F., WO2006/136304). A1899, a previously described Kv1.5 blocker (Peukert, S.,Brendel, J., Pirard, B., Brueggemann, A., Below, P., Kleemann, H.-W.,Hemmerle, H., Schmidt, W.; Identification, Synthesis, and Activity ofNovel Blockers of the Voltage-Gated Potassium Channel Kv1.5.; Journal ofMedicinal Chemistry (2003), 46(4), 486-498) has been stated to be aTASK-1 blocker (Streit, A. K.; Netter, M. F., Kempf, F., Walecki, M.,Rinne, S., Bollepalli, M. K.; Preisig-Mueller, R.; Renigunta, V.; Daut,J.; Baukrowitz, T.; Sansom, M. S. P.; Stansfeld, P. J.; Decher, N. ASpecific Two-pore Domain Potassium Channel Blocker Defines the Structureof the TASK-1 Open Pore; Journal of Biological Chemistry (2011),286(16), 13977-13984). Also arachidonamide anandamide (an endogenousligand of the cannabinoid receptor) and its methanandamide homolog havebeen described as TASK-1 blockers (Maingret F., Patel A. J., LazdunskiM., Honoré E.; The endocannabinoid anandamide is a direct and selectiveblocker of the background K+ channel TASK-1; EMBO J. 2001 (20), 47-54).Doxapram, which is used for the treatment of respiratory disorders hasbeen stated to be a TASK-1 blocker (Cotten J. F., Keshavaprasad B.,Laster M. J., Eger E. I., Yost C. S.; The Ventilatory Stimulant DoxapramInhibits TASK Tandem Pore (K_(2P)) Potassium Channel Function but DoesNot Affect Minimum Alveolar Anesthetic Concentration; Anesth. Analg.2006 (102) 779-785).

EP 0 086 422 A2 describes some N-acetylatedtetrahydro-1H-pyrazolo[4,3-c]pyridine compounds. However no biologicalactivity has been described for these compounds therein.

Thus, a goal of the present invention is to provide efficient TASK-1inhibitors suitable for the treatment and prevention of TASK-1 relatedconditions. The present invention relates to TASK-1 blockers of theformula I

wherein

-   A=(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising    1-3 heteroatoms selected from the group N, O and S,    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-,        (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   X═(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising    1-3 heteroatoms selected from the group N, O and S,    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-,        (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and        (C₁-C₆)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—;-   R2=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-;-   R3=H, (C₁-C₄)-alkyl-;-   R4=H, (C₁-C₄)-alkyl-;    or wherein R3 and R4 together form a (C₂-C₃)-alkylene bridge;-   R5=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—,    (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-,    (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-,    (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl,    heteroaryl-(C₁-C₆)-alkyl-, aliphatic heterocycle,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine, and    -   wherein the aliphatic heterocycle is selected from the group of        morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered        aliphatic heterocycles comprising an oxygen atom, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 to 3 substituents independently selected from the group        of F, OH, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and    -   wherein the heteroaryl residues are five- or six-membered ring        systems, comprising 1-3 heteroatoms selected from the group N, O        and S, and    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—;-   R6=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-,    -   wherein one hydrogen atom of the alkyl group may be replaced by        an OH or (C₁-C₆)-alkyl-O— residue, and    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine;-   R7=H, (C₁-C₆)-alkyl-;    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine,        and/or of a stereoisomeric form of the compound of the formula I        and/or mixtures of these forms, and/or their pharmaceutically        acceptable salts, and        with the proviso if R5 is methyl and R2, R3 and R4 are equal to        H and A is equal to 4-fluoro-phenyl, the residue X is not        phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl,        4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl,        3,4-dichlorophenyl, and        with the proviso if R5 is methyl and R2, R3 and R4 are equal to        H and X is a phenyl residue, the residue A is not phenyl,        4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl,        4-ethyloxy-phenyl, 3-trifluoromethyl-phenyl, 2-thiophenyl or        4-methylthiophenyl, and        with the proviso if R5 is methyl and R2 is methyl and R3 and R4        are equal to H and A is equal to 4-fluoro-phenyl, the residue X        is not phenyl.

A preferred embodiment of the present invention relates to compounds,wherein

-   A=phenyl or a five- or six-membered heteroaryl selected from the    group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,    thiophen-2-yl or thiophen-3-yl,    -   wherein phenyl and heteroaryl are optionally substituted with        1-3 rests selected independently from F, Cl, Br, CN,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   X=a five- or six-membered heteroaryl, comprising 1-3 heteroatoms    selected from the group N, O and S,    -   wherein the heteroaryl group is optionally substituted with 1-3        residues selected independently from F, Cl, Br, CN,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—,        (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—;-   R2=H, (C₁-C₄)-alkyl-, (C₃-C₆)-cycloalkyl-;-   R3=H, (C₁-C₂)-alkyl-;-   R4=H, (C₁-C₂)-alkyl-;    or wherein R3 and R4 together form a (C₂-C₃)-alkylene bridge;-   R5=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—,    (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-,    (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-,    (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl,    heteroaryl-(C₁-C₆)-alkyl-, aliphatic heterocycle,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine, and    -   wherein the aliphatic heterocycle is selected from the group of        morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered        aliphatic heterocycles comprising an oxygen atom, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 to 3 substituents independently selected from the group        of F, OH, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and    -   wherein the heteroaryl residues are five- or six-membered ring        systems, comprising 1-3 heteroatoms selected from the group N, O        and S, and    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—;-   R6=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-,    -   wherein one hydrogen atom of the alkyl group may be replaced by        an OH— or (C₁-C₆)-alkyl-O— residue, and    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine;-   R7=H, (C₁-C₆)-alkyl-;    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine,        and/or of a stereoisomeric form of the compound of the formula I        and/or mixtures of these forms, and/or their pharmaceutically        acceptable salts.

Preferred compounds are, wherein

-   A=phenyl,    -   wherein the phenyl residue is optionally substituted with 1-3        rests selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-,        (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   X=a five- or six-membered heteroaryl, selected from the group    consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,    thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl,    thiazol-5-yl,    -   wherein the heteroaryl group is optionally substituted with 1-3        residues selected independently from F, Cl, Br, CN,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—,        (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   R1=R5-C(═O)— or (C₁-C₂)-alkyl-SO₂—;-   R2=H, (C₁-C₂)-alkyl-, cyclopropyl-;-   R3=H, methyl-;-   R4=H, methyl-;    or wherein R3 and R4 together form an ethylene bridge;    and wherein-   R5=H, (C₁-C₄)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₂)-alkyl-O—,    (C₁-C₂)-alkyl-S—, (C₁-C₄)-alkyl-O-methyl-, HO—(C₁-C₂)-alkyl-,    (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-, phenyl, phenyl-(C₁-C₂)-alkyl-,    R7R6N—, heteroaryl, heteroaryl-(C₁-C₄)-alkyl-, aliphatic    heterocycle,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine, and    -   wherein the aliphatic heterocycle is selected from the group of        morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl,        tetrahydrofuranyl, and tetrahydropyranyl, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 or 2 substituents independently selected from the group        of F, OH, (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, and    -   wherein the phenyl residue is optionally substituted with 1-3        rests selected independently from F, Cl, Br, CF₃,        (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—    -   wherein the heteroaryl residues are selected from the group        consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,        thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl,        thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,        pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl,        pyridazin-4-yl, pyrazin-2-yl and pyrazin-3-yl, and    -   wherein the heteroaryl residues are optionally substituted with        1 or 2 rests selected independently from F, Cl, Br, CF₃,        (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—;-   R6=H, (C₁-C₄)-alkyl-, cyclopropyl,    -   wherein one hydrogen atom of the alkyl group may be replaced by        an OH, methoxy or ethoxy residue; and-   R7=H, methyl-, ethyl;    and/or of a stereoisomeric form of the compound of the formula I    and/or mixtures of these forms, and/or their pharmaceutically    acceptable salts.

Particularly preferred compounds are, wherein

-   A=phenyl,    -   wherein the phenyl residue is optionally substituted with 1 or 2        rests selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-,        CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, and (C₁-C₂)-alkyl-S—;-   X=a five- or six-membered heteroaryl, selected from the group    consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,    thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl,    thiazol-5-yl,    -   wherein these residues are optionally substituted with 1 or 2        residues selected independently from F, Cl, Br, CN,        (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃,        (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—;-   R1=R5-C(═O)— or (C₁-C₂)-alkyl-SO₂—;-   R2=H, methyl, ethyl, cyclopropyl;-   R3 and R4=H, and-   R5=methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,    tert.-butyl, cyclopropyl or cyclobutyl;    and/or of a stereoisomeric form of the compound of the formula I    and/or mixtures of these forms, and/or their pharmaceutically    acceptable salts.

A further preferred embodiment of the present invention relates tocompounds, wherein

-   A=a five- or six-membered heteroaryl, comprising 1-3 heteroatoms    selected from the group N, O and S,    -   wherein the heteroaryl is substituted with 1-3 residues selected        independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-,        (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   X=phenyl, thiophen-2-yl or thiophen-3-yl,    -   wherein these residues are optionally substituted with 1-3 rests        selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-,        (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and        (C₁-C₆)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—;-   R2=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-;-   R3=H, (C₁-C₄)-alkyl-;-   R4=H, (C₁-C₄)-alkyl-;    or wherein R3 and R4 together form a (C₂-C₃)-alkylene bridge;-   R5=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—,    (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-,    (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-,    (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl,    heteroaryl-(C₁-C₆)-alkyl-, aliphatic heterocycle,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine, and    -   wherein the aliphatic heterocycle is selected from the group of        morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered        aliphatic heterocycles comprising an oxygen atom, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 to 3 substituents selected from the group of F, OH,        (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and    -   wherein the heteroaryl residues are five- or six-membered ring        systems, comprising 1-3 heteroatoms selected from the group N, O        and S, and    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—;-   R6=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-,    -   wherein one hydrogen atom of the alkyl group may be replaced by        an OH— or (C₁-C₆)-alkyl-O— residue, and    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine;-   R7=H, (C₁-C₆)-alkyl-;    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine,        and/or of a stereoisomeric form of the compound of the formula I        and/or mixtures of these forms, and/or their pharmaceutically        acceptable salts,        with the proviso that A is not 4-methylthiophenyl if in        compounds of formula I R5 is methyl and R2, R3 and R4 are        hydrogen and X is phenyl.

Preferred compounds are, wherein

-   A=2-pyridyl, 3-pyridyl or 4-pyridyl,    -   wherein the pyridyl residues are substituted with 1 or 2        residues selected independently from F, Cl, Br, CN,        (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, and        (C₁-C₂)-alkyl-S—;-   X=phenyl, thiophen-2-yl or thiophen-3-yl,    -   wherein these residues are substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—,        (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—;-   R1=R5-C(═O)— or (C₁-C₂)-alkyl-SO₂—;-   R2=H, methyl, ethyl, cyclopropyl;-   R3 and R4=H; and-   R5=H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or    tert.-butyl or wherein-   R5=cyclopropyl, cyclobutyl, cyclopentyl or    (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-;    or wherein-   R5=(C₁-C₂)-alkyl-O—, (C₁-C₂)-alkyl-S—, or OCF₃,    or wherein-   R5=(C₁-C₄)-alkyl-O-methyl-, HO—(C₁-C₂)-alkyl-,    or wherein-   R5=phenyl or phenylmethyl-,    -   wherein the phenyl residues are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CF₃,        (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN, methyl-SO₂—;        or wherein,-   R5=R7R6N—, wherein    -   R6=H, (C₁-C₄)-alkyl-, cyclopropyl,        -   wherein one hydrogen atom of the alkyl group may be replaced            by an OH, methoxy or ethoxy residue; and    -   R7=H, methyl-, ethyl;        or wherein-   R5=heteroaryl, heteroaryl-(C₁-C₆)-alkyl-,    -   wherein the heteroaryl residues are selected from the group        consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,        thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl,        thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl,        pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl,        pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl,        pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and    -   wherein the heteroaryl residues are optionally substituted with        1 or 2 rests selected independently from F, Cl, Br, CF₃,        (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—;        or wherein-   R5=an aliphatic heterocycle,    -   wherein the aliphatic heterocycle is selected from the group of        morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl and        tetrahydrofuranyl, tetrahydropyranyl, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 or 2 substituents independently selected from the group        of F, OH, (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-;        and/or of a stereoisomeric form of the compound of the formula I        and/or mixtures of these forms, and/or their pharmaceutically        acceptable salts.

A further preferred embodiment of the present invention relates tocompounds, wherein

-   A is equal to phenyl,    -   wherein the phenyl residue is optionally substituted with 1-3        residues selected independently from F, Cl, Br, CN,        (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine, and-   X is equal to phenyl,    -   wherein the phenyl group is optionally substituted with 1, 2 or        3 residues selected independently from F, Cl, Br, CN,        (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S—,        (C₁-C₄)-alkyl-O—C(O)— and (C₁-C₄)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine, and-   R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—;-   R2=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-;-   R3=H, (C₁-C₄)-alkyl-;-   R4=H, (C₁-C₄)-alkyl-;    or wherein R3 and R4 together form a (C₂-C₃)-alkylene bridge;-   R5=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—,    (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-,    (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-,    (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl,    heteroaryl-(C₁-C₆)-alkyl-, aliphatic heterocycle,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine, and    -   wherein the aliphatic heterocycle is selected from the group of        morpholinyl, piperidinyl, pyrrolidinyl and 4 to 7 membered        aliphatic heterocycles comprising an oxygen atom, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 to 3 substituents selected from the group of F, OH,        (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and    -   wherein the heteroaryl residues are five- or six-membered ring        systems, comprising 1-3 heteroatoms selected from the group N, O        and S, and    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—;-   R6=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-,    -   wherein one hydrogen atom of the alkyl group may be replaced by        an OH— or (C₁-C₆)-alkyl-O— residue, and    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine;-   R7=H, (C₁-C₆)-alkyl-;    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine,        with the proviso if R5 is methyl and R2, R3 and R4 are equal to        H and A is equal to 4-fluoro-phenyl, the residue X is not        phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl,        4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl,        3,4-dichlorophenyl, and        with the proviso if R5 is methyl and R2, R3 and R4 are equal to        H and X is a phenyl residue, the residue A is not phenyl,        4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl,        4-ethyloxy-phenyl or 3-trifluoromethyl-phenyl, and        with the proviso if R5 is methyl and R2 is methyl and R3 and R4        are equal to H and A is equal to 4-fluoro-phenyl, the residue X        is not phenyl.

Preferred compounds are, wherein

-   A=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—;-   X=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—,        (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—,-   R1=R5-C(═O)— or methyl-SO₂—;-   R2=H, (C₁-C₂)-alkyl-, cyclopropyl-;-   R3=H, methyl-;-   R4=H, methyl-;    or wherein R3 and R4 together form an ethylene bridge; and wherein-   R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein    the heteroaryl residues are selected from the group consisting of    pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,    thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,    isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl,    pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl,    pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl,    pyrazin-2-yl and payrazin-3-yl, and    -   wherein these residues are optionally substituted with 1 or 2        residues selected independently from F, Cl, Br, CF₃, methyl,        ethyl, methoxy, ethoxy, CN, methyl-SO₂—,        or wherein-   R5 is equal to H;    or wherein-   R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or    (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-,    or wherein-   R5 is equal to (C₁-C₂)-alkyl-O—, (C₁-C₂)-alkyl-S—,    or wherein-   R5 is equal to (C₁-C₄)-alkyl-O-methyl-, HO—(C₁-C₂)-alkyl-,    or wherein-   R5 is equal to phenyl- or phenylmethyl-,    -   wherein the phenyl residues are optionally substituted with 1-3        residues selected independently from F, Cl, Br, CF₃,        (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN, methyl-SO₂—, and    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine;        or wherein-   R5 is equal to R7R6N—, wherein    -   R6=H, (C₁-C₄)-alkyl-, cyclopropyl-, wherein one hydrogen atom of        the alkyl group may be replaced by a hydroxy, methoxy or ethoxy        residue and    -   R7=H, methyl-, ethyl-        or wherein-   R5 is equal to an aliphatic heterocycle,    -   wherein the aliphatic heterocycle is selected from the group of        oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,        piperidinyl, pyrrolidinyl, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 or 2 substituents selected from the group of F, OH,        (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, and wherein one or more        hydrogen atoms of the alkyl groups may be replaced by fluorine;        and/or of a stereoisomeric form of the compound of the formula I        and/or mixtures of these forms, and/or their pharmaceutically        acceptable salts.

Particularly preferred compounds are, wherein

-   A=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—;-   X=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—,        (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—,-   R1=R5-C(═O)—;-   R2=H, (C₁-C₂)-alkyl-, cyclopropyl-;-   R3=H, methyl-;-   R4=H, methyl-;    or wherein R3 and R4 together form an ethylene bridge;    and wherein-   R5 is equal to (C₂-C₄)-alkyl,    and/or of a stereoisomeric form of the compound of the formula I    and/or mixtures of these forms, and/or their pharmaceutically    acceptable salts.

A further embodiment of the present invention are compounds of formulaI, wherein

-   A=(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising    1-3 heteroatoms selected from the group N, O and S,    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-,        (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   X═(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising    1-3 heteroatoms selected from the group N, O and S,    -   wherein aryl and heteroaryl are optionally substituted with 1-3        rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-,        (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and        (C₁-C₆)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine;-   R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—;-   R2=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-;-   R3=H, (C₁-C₄)-alkyl-;-   R4=H, (C₁-C₄)-alkyl-;    or R3, R4 together form a (C₂-C₃)-alkylene bridge;    and wherein-   R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein    the heteroaryl residues are five- or six-membered ring systems,    comprising 1-3 heteroatoms selected from the group N, O and S, and    -   wherein the heteroaryl residues are optionally substituted with        1-3 residues selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not pyrimidin-4-yl, pyridine-2-yl, 1-methyl-pyrazol-3-yl or        1-methyl-imidazol-2-yl,        or wherein R5 is methyl,    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 2,4-difluorophenyl residue A is not        pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl,        3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl,        2-fluoro-5-methoxy-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 3-cyanophenyl residue A is not a        4-fluorophenyl residue, and    -   with the proviso if in compounds of formula I R3 is methyl, R2        and R4 are hydrogen and X is a 2,4-difluoro-phenyl residue A is        not a 4-fluoro-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is phenyl A is not phenyl,        3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl,        4-methyl-phenyl, 4-ethyloxy-phenyl, 4-methyl-thiophenyl,        2-thiophenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and A is 4-fluoro-phenyl X is not phenyl,        2-chloro-phenyl, 3,4-dichloro-phenyl, 4-chloro-phenyl,        4-fluoro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl,        4-ethyloxy-phenyl, or 4-acetoxyphenyl, and    -   with the proviso if R5 is methyl and R2 is methyl and R3 and R4        are equal to H and A is equal to 4-fluoro-phenyl, the residue X        is not phenyl, and        or wherein-   R5 is equal to H, (C₂-C₆)-alkyl, CF₃, CF₂H, CFH₂,    -   wherein one or more hydrogen atoms of the alkyl residue may be        replaced by fluorine;        or wherein-   R5 is equal to (C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl-(C₁-C₄)-alkyl-, with the proviso if in compounds    of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl    residue R5 is not cyclopropyl,    or wherein-   R5 is equal to (C₁-C₄)-alkyl-O— or (C₁-C₄)-alkyl-S—,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine;        or wherein-   R5 is equal to (C₁-C₄)-alkyl-O—(C₁-C₂)-alkyl-, HO—(C₁-C₄)-alkyl-,    or wherein-   R5 is equal to phenyl-, phenyl-(C₁-C₄)-alkyl-,    -   wherein the phenyl residues are optionally substituted with 1-3        residues selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—, and        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methylsulfonyl-phenyl, 4-methylsulfonyl-phenyl;        or wherein-   R5 is equal to R7R6N—, wherein    -   R6=H, (C₁-C₄)-alkyl-, cyclopropyl-, wherein one hydrogen atom of        the alkyl group may be replaced by an OH, methoxy or ethoxy        residue and    -   R7=H, (C₁-C₂)-alkyl-,        or wherein-   R5 is equal to an aliphatic heterocycle,    -   wherein the aliphatic heterocycle is selected from the group of        oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,        piperidinyl, pyrrolidinyl, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 or 2 substituents selected from the group of F, OH,        (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-, and    -   wherein one or more hydrogen atoms of the alkyl groups may be        replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methyl-oxetan-3-yl, tetrahydrofuran-3-yl,        tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl.

Preferred compounds are, wherein

-   A=phenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl    or thiophen-3-yl,    -   wherein these residues are optionally substituted with 1 or 2        residues selected independently from F, Cl, Br, CN,        (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and        (C₁-C₂)-alkyl-S—;-   X=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—,        (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—,    -   or    -   pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,        thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,        -   wherein these residues are optionally substituted with 1 or            2 residues selected independently from F, Cl, Br, CN,            (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃,            (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—;-   R1=R5-C(═O)— or (C₁-C₂)-alkyl-SO₂—;-   R2=H, (C₁-C₂)-alkyl-, cyclopropyl-;-   R3=H, (C₁-C₂)-alkyl-;-   R4=H, (C₁-C₂)-alkyl-;    or wherein R3 and R4 together form an ethylene bridge;    and wherein-   R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein    the heteroaryl residues are selected from the group consisting of    pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,    thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,    isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl,    pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl,    pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl,    pyrazin-2-yl and payrazin-3-yl, and    -   wherein these residues are optionally substituted with 1 or 2        residues selected independently from F, Cl, Br, CF₃, methyl,        ethyl, methoxy, ethoxy, CN, methyl-SO₂—,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not pyrimidin-4-yl, pyridine-2-yl, 1-methyl-pyrazol-3-yl or        1-methyl-imidazol-2-yl,        or wherein R5 is methyl,    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 2,4-difluorophenyl residue A is not        pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl,        3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl,        2-fluoro-5-methoxy-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 3-cyanophenyl residue A is not a        4-fluorophenyl residue, and    -   with the proviso if in compounds of formula I R3 is methyl, R2        and R4 are hydrogen and X is a 2,4-difluoro-phenyl residue A is        not a 4-fluoro-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is phenyl A is not phenyl,        3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl,        4-methyl-phenyl, 4-ethoxy-phenyl, 2-thiophenyl,        4-methylthiophenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and A is 4-fluoro-phenyl X is not 2-chloro-phenyl,        3,4-dichloro-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl,        4-methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl or        4-ethoxy-phenyl, and        or wherein-   R5 is equal to H, (C₂-C₄)-alkyl, CF₃;    or wherein-   R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or    (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not cyclopropyl,        or wherein-   R5 is equal to (C₁-C₂)-alkyl-O— or (C₁-C₂)-alkyl-S—,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine;        or wherein-   R5 is equal to (C₁-C₄)-alkyl-O-methyl-, HO—(C₁-C₂)-alkyl-,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine;        or wherein        R5 is equal to phenyl-, phenyl-(C₁-C₂)-alkyl-,    -   wherein the phenyl residues are optionally substituted with 1-3        residues selected independently from F, Cl, Br, CF₃,        (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN, methyl-SO₂—, and    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methylsulfonyl-phenyl, 4-methylsulfonyl-phenyl;        or wherein-   R5 is equal to R7R6N—, wherein    -   R6=H, (C₁-C₄)-alkyl-, cyclopropyl-, wherein one hydrogen atom of        the alkyl group may be replaced by a hydroxy, methoxy or ethoxy        residue and    -   R7=H, methyl-, ethyl-        or wherein        R5 is equal to an aliphatic heterocycle,    -   wherein the aliphatic heterocycle is selected from the group of        oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,        piperidinyl, pyrrolidinyl, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 or 2 substituents selected from the group of F, OH,        (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, and    -   wherein one or more hydrogen atoms of the alkyl groups may be        replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methyl-oxetan-3-yl, tetrahydrofuran-3-yl,        tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl.        and/or of a stereoisomeric form of the compound of the formula I        and/or mixtures of these forms, and/or their pharmaceutically        acceptable salts.

Further preferred compounds are, wherein

-   A is equal to phenyl,    -   wherein the phenyl residue is optionally substituted with 1-3        residues selected independently from F, Cl, Br, CN,        (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine, and-   X is equal to phenyl,    -   wherein the phenyl group is optionally substituted with 1, 2 or        3 residues selected independently from F, Cl, Br, CN,        (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S—,        (C₁-C₄)-alkyl-O—C(O)— and (C₁-C₄)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine, and-   R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—;-   R2=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-;-   R3=H, (C₁-C₄)-alkyl-;-   R4=H, (C₁-C₄)-alkyl-;    or wherein R3 and R4 together form a (C₂-C₃)-alkylene bridge; and    wherein-   R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein    the heteroaryl residues are five- or six-membered ring systems,    comprising 1-3 heteroatoms selected from the group N, O and S, and    -   wherein the heteroaryl residues are optionally substituted with        1-3 residues selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—,        -   wherein one or more hydrogen atoms of the alkyl moieties may            be replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not pyrimidin-4-yl, pyridine-2-yl, 1-methyl-pyrazol-3-yl or        1-methyl-imidazol-2-yl,        or wherein R5 is methyl,    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 2,4-difluorophenyl residue A is not        pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl,        3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl,        2-fluoro-5-methoxy-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 3-cyanophenyl residue A is not a        4-fluorophenyl residue, and with the proviso if in compounds of        formula I R3 is methyl, R2 and R4 are hydrogen and X is a        2,4-difluoro-phenyl residue A is not a 4-fluoro-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is phenyl A is not phenyl,        3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl,        4-methyl-phenyl, 4-ethyloxy-phenyl, 4-methyl-thiophenyl,        2-thiophenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and A is 4-fluoro-phenyl X is not phenyl,        2-chloro-phenyl, 3,4-dichloro-phenyl, 4-chloro-phenyl,        4-fluoro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl,        4-ethyloxy-phenyl, or 4-acetoxyphenyl, and    -   with the proviso if in compounds of formula I R2 is methyl, R3        and R4 are hydrogen and A is 4-fluoro-phenyl, the residue X is        not phenyl, and        or wherein-   R5 is equal to H, (C₂-C₆)-alkyl, CF₃, CF₂H, CFH₂,    -   wherein one or more hydrogen atoms of the alkyl residue may be        replaced by fluorine;        or wherein-   R5 is equal to (C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl-(C₁-C₄)-alkyl-,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not cyclopropyl,        or wherein-   R5 is equal to (C₁-C₄)-alkyl-O— or (C₁-C₄)-alkyl-S—,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine;        or wherein-   R5 is equal to (C₁-C₄)-alkyl-O—(C₁-C₂)-alkyl-, HO—(C₁-C₄)-alkyl-,    or wherein-   R5 is equal to phenyl-, phenyl-(C₁-C₄)-alkyl-,    -   wherein the phenyl residues are optionally substituted with 1-3        residues selected independently from F, Cl, Br, CF₃,        (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—, and    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methylsulfonyl-phenyl, 4-methylsulfonyl-phenyl;        or wherein-   R5 is equal to R7R6N—, wherein    -   R6=H, (C₁-C₄)-alkyl-, cyclopropyl-, wherein one hydrogen atom of        the alkyl group may be replaced by an OH, methoxy or ethoxy        residue and    -   R7=H, (C₁-C₂)-alkyl-,        or wherein-   R5 is equal to an aliphatic heterocycle,    -   wherein the aliphatic heterocycle is selected from the group of        oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,        piperidinyl, pyrrolidinyl, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 or 2 substituents selected from the group of F, OH,        (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-, and    -   wherein one or more hydrogen atoms of the alkyl groups may be        replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methyl-oxetan-3-yl, tetrahydrofuran-3-yl,        tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl.-   R6=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-,    -   wherein one hydrogen atom of the alkyl group may be replaced by        an OH— or (C₁-C₆)-alkyl-O— residue, and    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine;-   R7=H, (C₁-C₆)-alkyl-;    -   wherein one or more hydrogen atoms of the alkyl group may be        replaced by fluorine.

Particularly preferred compounds are compounds of formula I, wherein

-   A=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—;-   X=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—,        (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—,-   R1=R5-C(═O)— or methyl-SO₂—;-   R2=H, (C₁-C₂)-alkyl-, cyclopropyl-;-   R3=H, methyl-;-   R4=H, methyl-;    or wherein R3 and R4 together form an ethylene bridge;    and wherein-   R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein    the heteroaryl residues are selected from the group consisting of    pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,    thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,    isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl,    pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl,    pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl,    pyrazin-2-yl and payrazin-3-yl, and    -   wherein these residues are optionally substituted with 1 or 2        residues selected independently from F, Cl, Br, CF₃, methyl,        ethyl, methoxy, ethoxy, CN, methyl-SO₂—,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not pyrimidin-4-yl, pyridine-2-yl, 1-methyl-pyrazol-3-yl or        1-methyl-imidazol-2-yl,        or wherein R5 is methyl,    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 2,4-difluorophenyl residue A is not        pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl,        3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl,        2-fluoro-5-methoxy-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is a 3-cyanophenyl residue A is not a        4-fluorophenyl residue, and    -   with the proviso if in compounds of formula I R3 is methyl, R2        and R4 are hydrogen and X is a 2,4-difluoro-phenyl residue A is        not a 4-fluoro-phenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and X is phenyl A is not phenyl,        3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl,        4-methyl-phenyl, 4-ethoxy-phenyl, 2-thiophenyl,        4-methylthiophenyl, and    -   with the proviso if in compounds of formula I R2, R3 and R4 are        hydrogen and A is 4-fluoro-phenyl X is not 2-chloro-phenyl,        3,4-dichloro-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl,        4-methyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl or        4-acetoxyphenyl, and    -   with the proviso if in compounds of formula I R2 is methyl, R3        and R4 are hydrogen and A is 4-fluoro-phenyl, the residue X is        not phenyl, and        or wherein-   R5 is equal to H, (C₂-C₄)-alkyl, CF₃;    or wherein-   R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or    (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not cyclopropyl,        or wherein-   R5 is equal to (C₁-C₂)-alkyl-O— or (C₁-C₂)-alkyl-S—,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine;        or wherein-   R5 is equal to (C₁-C₄)-alkyl-O-methyl-, HO—(C₁-C₂)-alkyl-,    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine;        or wherein-   R5 is equal to phenyl-, phenyl-(C₁-C₂)-alkyl-,    -   wherein the phenyl residues are optionally substituted with 1-3        residues selected independently from F, Cl, Br, CF₃,        (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN, methyl-SO₂—, and    -   wherein one or more hydrogen atoms of the alkyl moieties may be        replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methylsulfonyl-phenyl, 4-methylsulfonyl-phenyl;        or wherein-   R5 is equal to R7R6N—, wherein    -   R6=H, (C₁-C₄)-alkyl-, cyclopropyl-, wherein one hydrogen atom of        the alkyl group may be replaced by a hydroxy, methoxy or ethoxy        residue and    -   R7=H, methyl-, ethyl-        or wherein-   R5 is equal to an aliphatic heterocycle,    -   wherein the aliphatic heterocycle is selected from the group of        oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl,        piperidinyl, pyrrolidinyl, and    -   wherein the aliphatic heterocycle may be optionally substituted        with 1 or 2 substituents selected from the group of F, OH,        (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, and    -   wherein one or more hydrogen atoms of the alkyl groups may be        replaced by fluorine,    -   with the proviso if in compounds of formula I A is a        3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is        not 3-methyl-oxetan-3-yl, tetrahydrofuran-3-yl,        tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl,        and/or of a stereoisomeric form of the compound of the formula I        and/or mixtures of these forms, and/or their pharmaceutically        acceptable salts.

Further preferred compounds suitable as TASK-1 inhibitors are compoundsof formula I, wherein

-   A=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—;-   X=phenyl,    -   wherein the phenyl residue is substituted with 1 or 2 residues        selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃,        CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—,        (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—,-   R1=R5-C(═O)—;-   R2=H, (C₁-C₂)-alkyl-, cyclopropyl-;-   R3=H, methyl-;-   R4=H, methyl-;    or wherein R3 and R4 together form an ethylene bridge;    and wherein-   R5 is equal to (C₂-C₄)-alkyl;    and/or of a stereoisomeric form of the compound of the formula I    and/or mixtures of these forms, and/or their pharmaceutically    acceptable salts.

Alkyl radicals have between 1 and 6, preferably between 1 and 4 carbonatoms and may be straight-chain or branched. Alkyl radicals may also bestraight-chain or branched if they are substituted or are present inother radicals, for example in an alkyloxy radical (alkoxy radical) orin a fluorinated alkyl radical. Examples of alkyl radicals are methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.One or more, for example 1, 2, 3, 4, 5, 6, 7, 8, or 9 hydrogen atoms inalkyl radicals may be replaced by fluorine atoms. Preferred fluorinatedalkyl radicals are CF₃, CF₂H and CFH₂. Substituted alkyl radicals may besubstituted in any positions. Preferred alkyloxy radicals are methoxyand ethoxy. These explanations with respect to alkyl radicals applycorrespondingly to alkyl radicals which in the definition of a group inthe compounds of the formula I are bonded to two adjacent groups, orlinked to two groups, and may be regarded as divalent alkyl radicals(alkanediyl radicals, alkylene radicals), like in the case of the alkylpart of a substituted alkyl group, for example the group(C₁-C₆)-alkyloxy-(C₁-C₆)-alkyl- or the group heteroaryl-(C₁-C₆)-alkyl-,in which groups and likewise in other groups the terminal hyphen denotesthe free bond via which the group is bonded, and thus indicates viawhich subgroup a group composed of subgroups is bonded. Thus, suchradicals can also be straight-chain or branched, the bonds to theadjacent groups can be located in any positions and can start from thesame carbon atom or from different carbon atoms, and they can beunsubstituted or substituted by fluorine substituents independently ofany other substituents. Examples of such divalent alkyl radicals aremethylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene,2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene, etc.

Examples of cycloalkyl radicals having 3 to 6 C atoms are cyclopropyl,cyclobutyl, 1-methylcyclopropyl-, 2-methylcyclopropyl-, cyclobutyl,2-methylcyclobutyl-, 3-methylcyclobutyl-, cyclopentyl,2-methylcyclopentyl-, 3-methylcyclopentyl-, cyclohexyl etc.

Preferred heteroaryl residues are five or six-membered rings, comprising1 to 3 heteroatoms selected from the group N, O and S, wherein aheteroaryl ring preferably comprise only one O or S atom. Preferredheteroaryl groups are 2-thiophenyl, 3-thiophenyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl,3-pyrazolyl, 4-pyrazolyl, 2-imidazolyl, 4-imidazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl,5-isothiazolyl, wherein particularly preferred are 2-pyridyl, 3-pyridyland 4-pyridyl.

Preferred heteroaryl residues for the group A are unsubstituted orsubstituted pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yland thiophen-3-yl, particularly preferred are substituted heteroarylresidues.

Preferred heteroaryl residues for the group X are unsubstituted orsubstituted pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,thiophen-3-yl, thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, particularlypreferred are substituted heteroaryl residues.

Preferred heteroaryl residues for R5 are unsubstituted or substitutedpyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl,pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl,pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl,pyrazin-2-yl and payrazin-3-yl.

The heteroaryl residues may unsubstituted or substituted with one or twosubstituents. Preferred substituents of the heteroaryl residues are F,Cl, Br, methoxy, ethoxy, methyl, ethyl, NC—, CF₃O—, CF₃.

A preferred aryl residue is phenyl, wherein one or two hydrogen may bereplaced by substituents, preferably selected from the group F, CI,methoxy, ethoxy, methyl, ethyl, NC—, CF₃O—, CF₃, CH₃—SO₂—.

Preferred aliphatic heterocycle are selected from the group ofmorpholinyl, piperidinyl, pyrrolidinyl, oxetanyl and tetrahydrofuranyland tetrahydropyranyl, wherein these aliphatic heterocycle may beoptionally substituted with 1 or 2 substituents preferably selectedindependently from the group of F, OH, methoxy, ethoxy, methyl andethyl.

If a radical is disubstituted or trisubstituted, the substituents may beidentical or different.

If the compounds of the formula I comprise one or more basic groups orone or more basic heterocycles, the invention also includes thecorresponding physiologically acceptable salts includingtrifluoroacetates, in particular the pharmaceutically acceptable salts.Thus, the compounds of the formula I which have one or more basic, i.e.protonatable, groups or comprise one or more basic heterocyclic rings,can also be used in the form of their physiologically tolerated acidaddition salts with inorganic or organic acids, for example ashydrochlorides, phosphates, sulfates, methanesulfonates, acetates,lactates, maleates, fumarates, malates, gluconates etc. Salts can beobtained from compounds of the formula I by conventional processes, forexample by combining with an acid in a solvent or dispersant or else byanion exchange from other salts. The compounds of the formula I may alsobe deprotonated on an acidic group and be used for example as alkalimetal salts, preferably sodium or potassium salts, or as ammonium salts,for example as salts with ammonia or organic amines or amino acids.

The compounds of the formula I may exist in stereoisomeric forms. Thecenters of asymmetry which are present may independently of one anotherhave the S configuration or the R configuration. The invention includesall possible stereoisomers, for example enantiomers or diastereomers,and mixtures of two or more stereoisomeric forms, for exampleenantiomers and/or diastereomers, in any ratios. The invention thusincludes for example enantiomers in enantiopure form, both aslevorotatory and as dextrorotatory antipodes, and in the form ofmixtures of the two enantiomers in various ratios or in the form ofracemates. Individual stereoisomers can be prepared as desired byfractionating a mixture by conventional methods or for example bystereoselective synthesis.

For the preparation of the compounds of formula I the following methodscan be used.

In the described various chemical processes, the residues A, X, R1, R2,R3, R4, R5, R6 and R7 have the same meaning as in compounds of theformula I, provided that no specific definition of the respectiveresidue is mentioned.

The preparation of diverse 4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridineintermediates can be done according to Scheme 1 (method A) following apreviously described synthesis (EP 0 086 422 A2). The synthesis isapplicable to a large variety of different groups A. Thus, starting fromcommercially available 1-acetyl-4-piperidone1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (enamine 1) isobtained. Thus, morpholine is added to a solution of1-acetyl-4-piperidone in the presence of p-toluenesulfonic acidmonohydrate (catalytic PTSA). After acylation with commerciallyavailable acyl chlorides, followed by acidic aqueous hydrolysis thediketones 2 are obtained and can be subjected to ring-closure withhydrazine hydrate to give the corresponding diverse4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine intermediates 3.

The acyl chlorides can alternatively be prepared by standard proceduresfrom the corresponding acids e.g. by reaction with thionyl chloride inthe presence of catalytic amounts of DMF (see for example Dalisay, D.S.; Quach, T.; Nicholas, G. N.; Molinski, T. F., Angewandte Chemie,International Edition, 2009, vol. 48, 4367-4371). If A is a heteroarylthan sometimes an alternative synthesis is preferable and can be used asshown in Scheme 1 (method B). Thus starting from commercially availableacids the mixed anhydrides are formed by reaction withisobutylchloroformate. 1-Acetyl-4-piperidone1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone can bedeprotonated with strong bases like lithium hexamethyldisilazide andreacted with the mixed anhydride described above. The diketones 2 areobtained and can be subjected to ring-closure with hydrazine hydrate togive the corresponding diverse4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine intermediates 3.

R3, R4 substituted intermediates 5 can be accorded similarly as shown inScheme 2. Thus after acetylation of commercially available or knownpiperidones N-Acetyl-piperidones 4 are obtained. They can bedeprotonated with strong bases like lithium diisopropylamide (LDA) andreacted with mixed anhydrides formed by reaction of aryl orheteroarylcarbonic acids and isobutylchloroformate as described above.The diketones obtained can be subjected to ring-closure with hydrazinehydrate to give the corresponding R3, R4 substituted4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine intermediates 5.

4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine intermediates can besuccessfully alkylated with a range of different aryl- and heteroarylhalogenides by heating in the presence of an excess amount of a baselike K₂CO₃ in an inert solvent like CH₃CN as shown in Scheme 3. Thecorresponding substituted 4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridineintermediates 6 were found to be TASK-1 blockers.

In a different approach (Scheme 4), starting from Boc-protectedpiperidones, the diketones obtained after deprotonation by a strong baselike lithium diisopropylamide and reaction with diverse acyl chloridescan be reacted with substituted benzylhydrazines and subsequentlydeprotected to give compounds 7 which are intermediates in the synthesisof TASK-1 blockers.

The group R1 of compounds of formula I can be varied synthetically asshown in Scheme 5. The N-acetyl group can be cleaved by heating anacidic aqueous solution of compounds 6, for example in a mixture ofethanol and 2N aqueous HCl. The corresponding amines 7 can be modifiedin a variety of ways, for example by acylation as shown in Scheme 6.This can be done by several methods: for example by reaction withcarboxylic acids in the presence of 1-hydroxybenzotriazole and EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) (Nozaki,S. J. Peptide Res. 1999, 54, 162) (method A) or TOTU(O-[(Ethoxycarbonyl)cyanomethylenamino]-N,N,N′,N-tetramethyluroniumtetrafluoroborate) (Knorr, R. et al. Tetrahedron Lett. 1989, 30, 1927)(method D), by reaction with acyl chlorides or alkyl chloroformates inthe presence of K₂CO₃ in CH₃CN (method B), in a “Schotten-Baumann”reaction type by reaction with acyl chlorides in a water-ethyl acetatemixture in the presence of NaHCO₃ (method C), by reaction with acylchlorides in the presence of triethylamine in CH₂Cl₂ (method E), or byreaction with acetic anhydride in pyridine (method F). The group R5 maycarry protecting groups which can be cleaved off by methods known in theprior art. For example a hydroxyl group in R5 can be protected as atert-butylether which can be cleaved off by an acid like HCl to givedeprotected compounds 14 (Scheme 11). Of course the reaction is broadlyapplicable and not limited to the exact structure shown in Scheme 11.

Alternatively TASK-1 blockers 8 can be obtained by sulfonylation withalkylsulfonyl halogenides ((C₁-C₆)-alkyl-SO₂—) in inert solvents likeCH₂Cl₂ in the presence of a base like triethylamine as shown in Scheme7.

In another reaction (Scheme 8), reaction of intermediates 7 with diverseisocyanates in an inert solvent for example CH₂Cl₂ leads to formation ofureas 11 which have been found to be TASK-1 blockers.

In another reaction (Scheme 9), reaction of intermediates 7 with4-nitrophenylchloroformate leads to intermediates with can be reactedwith diverse amines to give ureas 12 which have been found to be TASK-1blockers and are novel compounds not described before.

The aryl or heteroaryl ring A can be modified when substituted by abromide to give the corresponding nitriles as shown in Scheme 10 byreaction with Zn(CN)₂ in the presence of a catalytic amount oftetrakis(triphenylphosphine)palladium (0) (in analogy to Alterman, M.;Anders, H. Journal of Organic Chemistry, 2000, vol. 65, 23 p.7984-7989). The reaction is not limited to pyridines as drawn in Scheme10 but is applicable to a range of aryl and heteroaryl systems. Thenovel compounds 13 which have not been previously described have beenfound to be TASK-1 blockers.

A tert-butylether 8 can be cleaved off by an acid like HCl to givedeprotected compounds 14 (Scheme 11). The reaction is broadly applicableand not limited to the exact structure shown in Scheme 11.

The working up and, if desired, the purification of the products and/orintermediates takes place by conventional methods such as extraction,chromatography or crystallization and conventional dryings.

Owing to the TASK-1-inhibitory properties, the compounds of the formulaI and/or their pharmaceutically compatible salts are suitable for theprevention and treatment of disorders which are caused by activation orby an activated TASK-1, and also of disorders in which haveTASK-1-related damages appear secondary to another, primary cause.

The compounds of the formula I, and/or physiologically compatible saltsthereof can also be used for the treatment and prevention of disorderswhere TASK-1 requires only partial inhibition, for example by using alower dosage,

wherein for the treatment and prevention of disorders described belowthe compounds of formula I includes

-   -   compounds wherein R5 is methyl and R2, R3 and R4 are equal to H        and A is equal to 4-fluoro-phenyl, and the residue X is phenyl,        4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl,        4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl,        3,4-dichlorophenyl, and    -   compounds wherein R5 is methyl and R2, R3 and R4 are equal to H        and X is a phenyl residue, and the residue A is phenyl,        4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl,        4-ethyloxy-phenyl, 3-trifluoromethyl-phenyl, 2-thiophenyl or        4-methylthiophenyl, and    -   compounds wherein R5 is methyl and R2 is methyl and R3 and R4        are equal to H and A is equal to 4-fluoro-phenyl and the residue        X is phenyl.

These compounds can be employed to produce medicaments with a TASK-1channel-blocking effect for the therapy and prophylaxis of TASK-1channel-mediated diseases. The compounds of the formula I and/or theirpharmaceutically acceptable salts can further be used for the therapy orprophylaxis of cardiac arrhythmias, e.g. of arrhythmias that respond tothe changes in the shape of the action potential, mainly a prolongationof the action potential, which is induced by TASK-1 blockade.

The compounds of the formula I and/or their pharmaceutically acceptablesalts can be employed for terminating existent atrial fibrillation orflutter to restore the sinus rhythm (cardioversion). In addition, thecompounds reduce the susceptibility for a new development of atrialfibrillation events, thus the compounds are suitable for prophylactictreatment by maintenance of sinus rhythm (rhythm control). Thesubstances are devoid of a ventricular proarrhythmic risk (prolongationof the QT-interval and Torsades de pointe arrhythmias).

The compounds of the formula I and/or their pharmaceutically acceptablesalts can be employed for producing a medicament for the treatmentand/or prevention of arrhythmias, particularly atrial trachyarrhythmias,atrial fibrillation and atrial flutter

The compounds of the formula I and/or their pharmaceutically acceptablesalts are further suitable for producing a medicament for the therapy orprophylaxis of sleep-related respiratory disorders, central andobstructive sleep apneas, upper airway resistance syndrome,Cheyne-Stokes respiration, snoring, disrupted central respiratory drive,sudden child death, postoperative hypoxia and apnea, muscle-relatedrespiratory disorders, respiratory disorders after long-term mechanicalventilation (weaning), respiratory disorders during adaptation in highmountains, acute and for respiratory disorders, chronic lung disorderswith hypoxia and hypercapnia, chronic obstructive pulmonary disease(COPD) and obesity hypoventilation syndrome.

The compounds of the formula I and/or their pharmaceutically acceptablesalts are further suitable as a respiratory stimulant for the preventionand treatment of respiratory depression associated with anesthesia orprocedural sedations for small interventions or for diagnostic purposes,for the treatment and prevention of respiratory depression by opioids inchronic pain treatment e.g. in cancer or palliative care or proceduralsedations and/or for weaning from longterm mechanical ventilation.

The compounds of the formula I and/or their pharmaceutically acceptablesalts are further suitable for the treatment and/or prevention ofmultiple sclerosis and inflammatory and degenerative disorders of thecentral nervous system.

The compounds of the invention of the formula I and theirpharmaceutically acceptable salts can thus be used on animals,preferably on mammals, and in particular on humans, as pharmaceuticalson their own, in mixtures with one another or in the form ofpharmaceutical preparations (pharmaceutical compositions).

Thus, a further embodiment of the present invention is a pharmaceuticalpreparation comprising an effective amount of a compound of the formulaI and/or of its pharmaceutically acceptable salts, together withpharmaceutically acceptable carriers and additives, alone or incombination with other pharmacological active ingredients orpharmaceuticals. The pharmaceutical preparations usually comprise from0.1 to 90 percent by weight of the compounds of the formula I and/ortheir pharmaceutically acceptable salts. The pharmaceutical preparationscan be produced in a manner known per se. For this purpose, thecompounds of the formula I and/or their pharmaceutically acceptablesalts are converted together with one or more solid or liquidpharmaceutical vehicles and/or excipients and, if desired, incombination with other pharmaceutical active ingredients into a suitabledosage form, which can then be used as pharmaceutical in human medicineor veterinary medicine.

Pharmaceuticals which comprise a compound of the formula I and/or itspharmaceutically acceptable salts can moreover be administered forexample orally, intravenously, intramuscular, subcutaneously, nasally,topically, pharyngeally or by inhalation, and the preferredadministration depends on the individual case, for example on theparticular manifestation of the disorder. The compounds of the formula Ican moreover be used alone or together with pharmaceutical excipients,in particular both in veterinary and in human medicine. Thepharmaceuticals comprise active ingredients of the formula I and/ortheir pharmaceutically acceptable salts generally in an amount of from0.01 mg to 1 g per dose unit.

The skilled worker is familiar on the basis of his expert knowledge withwhich excipients are suitable for the desired pharmaceuticalformulation. Besides solvents, gel formers, suppository bases, tabletexcipients and other active substance carriers it is possible to use forexample antioxidants, dispersants, emulsifiers, antifoams, maskingflavors, preservatives, solubilizers, agents for achieving a depoteffect, buffer substances or colorants.

For a form for oral use, the active compounds are mixed with theadditives suitable for this purpose, such as carriers, stabilizers orinert diluents, and converted by conventional methods into suitablepresentations such as tablets, coated tablets, two-piece capsules,aqueous, alcoholic or oily solutions. Examples of inert carriers whichcan be used are gum arabic, magnesia, magnesium carbonate, potassiumphosphate, lactose, glucose or starch, especially corn starch.Preparation can take place both as dry and as wet granules. Suitable asoily carriers or as solvents are, for example, vegetable or animal oilssuch as sunflower oil or fish liver oil. Suitable solvents for aqueousor alcoholic solutions are, for example, water, ethanol or sugarsolutions or mixtures thereof. Examples of further excipients, also forother administration forms, are polyethylene glycols and polypropyleneglycols.

For subcutaneous, intramuscular or intravenous administration, theactive compounds are converted if desired with the substances usual forthis purpose, such as solubilizers, emulsifiers or further excipients,into a solution, suspension or emulsion. The compounds of the formula Iand/or their pharmaceutically acceptable salts may also be lyophilizedand the resulting lyophilizates be used, for example, for producingproducts for injection or infusion. Examples of suitable solvents are:water, physiological saline or alcohols, for example ethanol, propanol,glycerol, as well as sugar solutions such as glucose or mannitolsolutions, or else mixtures of the various solvents mentioned.

Suitable as pharmaceutical formulation for administration in the form ofaerosols or sprays are, for example, solutions, suspensions or emulsionsof the active ingredient of the formula I or their pharmaceuticallyacceptable salts in a pharmaceutically acceptable solvent, such as inparticular ethanol or water, or a mixture of such solvents. Theformulation may if required also comprise other pharmaceuticalexcipients such as surfactants, emulsifiers and stabilizers, and apropellant gas. Such a preparation comprises the active ingredientnormally in a concentration of about 0.1 to 10, in particular of about0.3 to 3 percent by weight.

The dosage of the active ingredient to be administered or of thepharmaceutically acceptable salts thereof depends on the individual caseand should be adapted to the circumstances of the individual case asusual for an optimal effect. Thus, it naturally depends on the frequencyof administration and on the potency and duration of action of theparticular compounds employed for therapy or prophylaxis, but also onthe type and severity of the disease to be treated, and on the gender,age, weight and individual response of the human or animal to betreated, and on whether therapy is acute or prophylactic.

The daily dose of a compound of the formula I and/or itspharmaceutically acceptable salts for a patient weighing about 75 kg isnormally at least 0.001 mg/kg to 100 mg/kg of body weight, preferably0.01 mg/kg to 20 mg/kg. Even higher dosages may also be necessary foracute episodes of the disease, for example in an intensive care unit. Upto 800 mg per day may be necessary. The dose may be in the form of asingle dose or be divided into a plurality, for example two, three orfour, single doses. Parenteral administration by injection or infusion,for example a continuous intravenous infusion, may also be advantageous,especially in the treatment of acute cases of cardiac arrhythmias, forexample in an intensive care unit.

EXAMPLES

The following examples illustrate the various embodiments of the presentinvention and are part of the present invention.

1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1)

According to Scheme 1, step 1: a mixture of morpholine (67.85 g, 0.779mol), 1-acetyl-4-piperidone (99.95 g, 0.708 mol) andpara-toluenesulfonic acid (0.366 g, 2.1 mmol) in toluene (300 ml) washeated in a Dean-Stark trap apparatus for 16 h at reflux. Solvents wereevaporated in vacuo to give 149 g of1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) which wasused in the next step without any further purification.

3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile(3a)

According to Scheme 1, method A: steps 2-3: to a solution of1-(4-Morpholin-4-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (1) (6.35 g,30.2 mmol) in dry dichloromethane (30 ml) at 0° C. was addedtriethylamine (3.056 g, 30.2 mmol) and after stirring the solution at 0°C. for 10 min, 3-cyanobenzoyl chloride (5 g, 30.2 mmol) was added. Themixture was stirred for 45 min at 0° C. then the mixture was allowed towarm to room temperature and stirred overnight. 5% aqueous HCl was addedand the mixture was stirred for 2 h. The mixture was extracted withdichloromethane and the organic layer was washed with water, filteredover a short pad of silica gel and evaporated to dryness to give 8 g of3-(1-Acetyl-4-oxo-piperidine-3-carbonyl)-benzonitrile (2a) which wasused immediately in the next step without purification.

To a mixture of 3-(1-Acetyl-4-oxo-piperidine-3-carbonyl)-benzonitrile(2a) (8 g, 29.6 mmol) in ethanol (26 ml) at 10° C. hydrazine hydrate(4.44 g, 88.8 mmol) was added slowly within 5 min. The mixture wasstirred 3 h and allowed to warm to room temperature overnight. Themixture was concentrated to ¼ of its volume until a precipitate formed.The suspension was stirred for 2 h, cooled down and filtrated. The solidwas washed with a small amount of ethanol. A second portion of productprecipitated overnight from the filtrate and was pooled with the firstportion of solid to give 4.02 g of3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile(3a) as a solid.

R_(t)=1.20 min (LC-method 7). Detected mass: 267.15 [M+H₊]

1-[3-(4-Trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(3m)

According to Scheme 1, method B: to a solution of4-(trifluoromethyl)-2-pyridinecarboxylic acid (0.42 g, 1.54 mmol) in drytetrahydrofuran was added N-methylmorpholine (163 mg, 1.62 mmol) andisobutylchloroformate (221 mg, 1.62 mmol) and the mixture was stirredfor 30 min at room temperature and the solid was filtered off. Thefiltrate was used in the subsequent reaction.

To a solution of 1-acetyl-4-piperidone (0.207 g, 1.466 mmol) intetrahydrofuran at 0° C. was added dropwise 1M lithiumbis(trimethyldisilazide) in tetrahydrofuran (1.54 mmol, 1.54 ml) and themixture was stirred for 15 min at 0° C., then the mixture was cooleddown to −78° C. The mixed anhydride solution generated above was addedto this mixture at −78° C., the mixture was allowed to warm to roomtemperature and stirred for 90 min. To this mixture at 10° C. was addedethanol (5 ml) and hydrazine hydrate (0.603 g, 7.72 mmol) and themixture was stirred 16 h at room temperature. The mixture wasconcentrated and after addition of CH₂Cl₂ and aqueous NaHCO₃ the mixturewas extracted 3 times with CH₂Cl₂, the combined organic layers werewashed with brine, dried over NaCl, filtrated and the filtrate wasevaporated to dryness to give 323 mg of1-[3-(4-Trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(3m). The product was used crude in the next reaction steps withoutfurther purification.

R_(t)=1.61 min (LC-method 1). Detected mass: 311.18 [M+H₊]

The examples in the following table were obtained according to Scheme 1,Method A or Method B as specified, from the specified starting compound(SC) (by following a similar procedure as used for the synthesis of(3a); in part the compounds were purified by reverse phase HPLC(CH₃CN/water gradient with 0.1% trifluoroacetic acid).

R_(t)/[min] Comp. (LC- No. Starting Meth.) (Meth.) Comp. ProductChemical Name [M + H⁺] 3b (A) 4-fluoro- benzoyl chloride

1-[3-(4-Fluoro- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 2.32 (8) 260.12 3c (A) 6-(tri- fluoro-methyl)- pyridine- 2- carbonyl chloride

1-[3-(6-Trifluoro- methyl-pyridin- 2-yl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.10 (4) 311.2 3d (A) 3-Trifluoro methyl- benzoyl chloride

1-[3-(3-Trifluoro- methyl-phenyl)- 1,4,6,7-tetra- hydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.12 (4) 310.11 3e (A) 3- Trifluoromethoxy- benzoyl chloride

1-[3-(3- Trifluoro- methoxy- phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 3.60 (2) 326.16 3f (A) 3-chloro- benzoylchloride

1-[3-(3-Chloro- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 0.94 (4) 275.08 3g (A) 2-Fluoro- 5-methoxy-benzoyl chloride

1-[3-(2-Fluoro- 5-methoxy- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 2.97 (2) 290.15 3h (A) 3- methoxy- benzoylchloride

1-[3-(3- Methoxy- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 0.99 (4) 272.5 3i (A) 4-Fluoro- 3-methoxy-benzoyl chloride

1-[3-(4-Fluoro- 3-methoxy- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 1.02 (4) 290.2 3j (A) 4-Fluoro- 3-cyano-benzoyl chloride

5-(5-Acetyl- 4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl)-2-fluoro- benzonitrile 1.01 (4) 285.1 3k (A) 3-Fluoro- benzoyl chloride

1-[3-(3-Fluoro- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 1.47 (9) 260.16 3l (A) 4- Trifluoro methyl-benzoyl chloride

1-[3-(4- Trifluoromethyl- phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.00 (4) 309.9 3n (B) 4-Bromo- pyridine- 2-carbonyl chloride

1-[3-(4-Bromo- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 0.91 (1) 321.09 3o (B) 2-Bromo- iso-nicotinoyl chloride

1-[3-(2-Bromo- pyridin-4-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 0.81 (1) 321.06 3p (B) 5-Bromo- nicotinoylchloride

1-[3-(5-Bromo- pyridin-3-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 0.96 (4) 321.12 3q (A) 3-Methyl- benzoylchloride

1-(3-m-Tolyl- 1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl)-ethanone 0.92 (1) 256.18 3r (B) 6-Methyl- pyridine- 2- carbonyl chloride

1-[3-(6-Methyl- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 0.74 (1) 257.11 3s (A) 6-Bromo- pyridine- 2-carbonyl chloride

1-[3-(6-Bromo- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 1.06 (4) 321.1 3t (B) 4-Methyl- pyridine- 2-carbonyl chloride

1-[3-(4-Methyl- pyridin-2-yl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone nd (nd) nd 3u (A) 6- Methoxy- pyridine-2-carbonyl chloride

1-[3-(6-Methoxy- pyridin-2- yl)-1,4,6,7-tetra- hydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone 0.9 (1) 273.15 3v (A) 6-Chloro-5-methoxy- pyridine- 2-carbonyl chloride

1-[3-(6-Chloro- 5-methoxy- pyridin-2-yl)- 1,4,6,7-tetra- hydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.02 (4) 307.1 3w (B) 3-Methyl- pyridine-2-carbonyl chloride

1-[3-(3-Methyl- pyridin-2-yl)- 1,4,6,7-tetra- hydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone nd (nd) nd 3x (A) 4- Methoxy- pyridine-2-carbonyl chloride

1-[3-(4- Methoxy- pyridin-2-yl)- 1,4,6,7-tetra- hydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone 0.55 (1) 273.16 3y (A) Thio- phene-2-carbonyl chloride

1-(3-Thiophen- 2-yl-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl)-ethanone 0.94 (4) 248.08 3z (A) 5-Chloro- thio- phene-2- carbonylchloride

1-[3-(5-Chloro- thiophen-2-yl)- 1,4,6,7-tetra- hydro-pyrazolo[4,3-c]pyridin-5- yl]-ethanone 1.07 (4) 282.02 3aa (A) Thio- phene-3-carbonyl chloride

1-(3-Thiophen- 3-yl-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl)-ethanone 0.93 (4) 248.05

8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a)

According to Scheme 2, Step 1:

A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in aceticanhydride was stirred at 70° C. for 3 h. Water was added, the mixturewas boiled for 30 min and cooled down to room temperature. CH₂Cl₂ and 1Naqueous NaOH was added until pH 9 was reached. The mixture was extracted2 times with CH₂Cl₂, the combined organic layers were dried over Na₂SO₄,filtrated and the solution was evaporated to dryness to give 0.7 g of8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a).

R_(t)=1.76 min (LC-method 2). Detected mass: 168.24 [M+H₊]

1-(3-Phenyl-4,5,11-triaza-tricyclo[6.2.1.0*2,6*]undeca-2(6),3-dien-11-yl)-ethanone (5a)

According to Scheme 2, Steps 2+3:

To a mixture of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a) (350 mg,2.1 mmol) in dry tetrahydrofuran at 0° C. was added 1N lithiumhexamethyldisilazide (2.2 ml, 2.2 mmol) and after 5 min the mixture wascooled to −78° C.

To a solution of 3-cyanobenzoic acid (323 mg, 2.2 mmol) andN-methyl-morpholine (232 mg, 2.3 mmol) in tetrahydrofuran was addedisobutylchloroformate (300 mg, 2.2 mmol). The mixture was stirred for 5min at 25° C., filtrated and washed with dry tetrahydrofuran. Thissolution was added dropwise to the −78° C. mixture above and the mixturewas then allowed to warm to 25° C. for 1 h. Solvents were evaporated,CH₂Cl₂ and water were added, the organic layer was dried over Na₂SO₄,filtrated and the solution was evaporated to dryness, redissolved inethanol (10 ml).

Hydrazine hydrate (245 mg, 3.14 mmol) was added and the solution wasstirred for min. Solvents were evaporated and the crude product waspurified by silica gel chromatography (dichloromethane/methanol 100/0 to70/30) to give 45 mg of1-(3-Phenyl-4,5,11-triaza-tricyclo[6.2.1.0*2,6*]undeca-2(6),3-dien-11-yl)-ethanone(5a).

R_(t)=1.01 min (LC-method 4). Detected mass: 293.18 [M+H₊]

1-[3-(4-Fluoro-phenyl)-4,5,11-triaza-tricyclo[6.2.1.0*2,6*]undeca-2(6),3-dien-1l-yl]-ethanone (5b)

1-[3-(4-Fluoro-phenyl)-4,5,11-triaza-tricyclo[6.2.1.0*2,6*]undeca-2(6),3-dien-1l-yl]-ethanone (5b) was obtained by following a similar reaction as usedfor synthesis of (5a).

R_(t)=1.06 min (LC-method 4). Detected mass: 286.18 [M+H₊]

3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(6a)

According to Scheme 3:

A mixture of3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile(3a) (0.48 g, 1.8 mmol), 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol)and K₂CO₃ (498 mg, 3.6 mmol) in 14 ml CH₃CN was stirred at 80° C. for 16h. A second portion of 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol)was added and the mixture was stirred for additional 7 h. Water wasadded, the mixture was extracted 3 times with ethyl acetate, thecombined organic layers were dried over MgSO₄, filtrated and thesolution was evaporated to dryness. The crude product was crystallizedfrom 10 ml 2-propanol and dried in vacuo to give 0.364 g of3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(6a).

R_(t)=1.62 min (LC method 7). Detected mass: 393.15 [M+H₊].

The examples in the following table were obtained according to Scheme 4by following a similar reaction as used for synthesis of (6a). Thecorresponding halogenides used (Hal-CH₂—X; particularly thecorresponding bromides or chlorides) are obvious to the man skilled inthe art and were commercially available. Reaction conditions variedslightly by reaction time (1-3 days), temperature (50-80° C.).

Products were routinely purified by reverse phase HPLC (CH₃CN/watergradient with 0.1% trifluoroacetic acid).

R_(t)/[min] (LC- Comp. Method) No. SC Product Chemical Name [M + H⁺] 6b3d

1-[1-(6-Chloro- pyridin-3-ylmethyl)- 3-(3-trifluoromethyl-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone1.26 (4) 435.09 6c 3d

1-[1-(4-Chloro- pyridin-3-ylmethyl)- 3-(3-trifluoromethyl-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone1.22 (4) 435.09 6d 3d

1-[1-(3-Methyl- pyridin-2-ylmethyl)- 3-(3-trifluoromethyl-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone3.97 (2) 415.28 6e 3b

1-[1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 2.29 (15) 350.16 6f 3b

1-[1-(2,4-Difluoro- benzyl)-3-(4-fluoro- phenyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.35 (12) 386.02 6g 3c

1-[1-(4-Fluoro- benzyl)-3-(6- trifluoromethyl- pyridin-2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.31 (4)419.17 6h 3m

1-[1-(2,4-Difluoro- benzyl)-3-(4- trifluoromethyl- pyridin-2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.02 (9)437.23 6i 3c

1-[1-(2,4-Difluoro- benzyl)-3-(6- trifluoromethyl- pyridin-2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.3 (4)437.15 6j 3n

1-[3-(4-Bromo- pyridin-2-yl)-1-(2,4- difluoro-benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.2 (1)447.1 6k 3o

1-[3-(2-Bromo- pyridin-4-yl)-1-(2,4- difluoro-benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.12 (1)447.14 6m 3p

1-[3-(5-Bromo- pyridin-3-yl)-1-(2,4- difluoro-benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.24 (4)447.2 6n 5a

3-[11-Acetyl-5-(2,4- difluoro-benzyl)- 4,5,11-triaza-tricyclo[6.2.1.02,6] undeca-2(6),3-dien- 3-yl]-benzonitrile 1.25 (4)419.21 6o 5b

1-[5-(2,4-Difluoro- benzyl)-3-(4-fluoro- phenyl)-4,5,11- triaza-tricyclo[6.2.1.02,6]undeca- 2(6),3-dien-11-yl]- ethanone 1.26 (4) 412.17 6p 3q

1-[1-(6-Chloro- pyridin-3-ylmethyl)- 3-m-tolyl-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.2 (4) 381.12 6q 3d

1-[1-(4-Methoxy- pyridin-2-ylmethyl)- 3-(3-trifluoromethyl-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone3.25 (2) 431.3 6r 3q

1-[1-(4-Chloro- pyridin-3-ylmethyl)- 3-m-tolyl-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.16 (4) 381.11 6s 3d

1-[1-(3-Methoxy- pyridin-2-ylmethyl)- 3-(3-trifluoromethyl-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone4.04 (2) 431.3 6t 3f

1-[3-(3-Chloro- phenyl)-1-(3- methyl-pyridin-2- ylmethyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.1 (1) 381.12 6u 3c

1-[1-[1-(4-Fluoro- phenyl)-ethyl]-3-(6- trifluoromethyl- pyridin-2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.35 (4)433.14 6v 3r

1-[1-(2,4-Difluoro- benzyl)-3-(6- methyl-pyridin-2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 3.15 (2)383.23 6w 3s

1-[3-(6-Bromo- pyridin-2-yl)-1-(2,4- difluoro-benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.3 (4)447.17 6x 3t

1-[1-(2,4-Difluoro- benzyl)-3-(4- methyl-pyridin-2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 0.97 (1)383.2 6y 3u

1-[1-(2,4-Difluoro- benzyl)-3-(6- methoxy-pyridin-2- yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.15 (1) 399.19 6z3v

1-[3-(6-Chloro-5- methoxy-pyridin-2- yl)-1-(2,4-difluoro-benzyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone1.25 (4) 433.11 6ab 3w

1-[1-(2,4-Difluoro- benzyl)-3-(3- methyl-pyridin-2-yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.14 (4)383.1 6ac 3x

1-[1-(2,4-Difluoro- benzyl)-3-(4- methoxy-pyridin-2- yl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.75 (2) 399.26 6ad3d

1-[1-(2-Methyl- thiazol-4-ylmethyl)- 3-(3-trifluoromethyl-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone1.23 (4) 421.12 6ae 3d

1-[1-Thiazol-2- ylmethyl-3-(3- trifluoromethyl- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.2 (4) 407.07 6af3y

1-[1-(2,4-Difluoro- benzyl)-3-thiophen- 2-yl-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.22 (4) 374.07 6ag 3q

1-[1-(5-Chloro- thiophen-2- ylmethyl)-3-m-tolyl- 1,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.3 (4) 386.08 6ah 3d

1-[1-(5-Chloro- thiophen-2- ylmethyl)-3-(3- trifluoromethyl-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone1.35 (4) 440.07 6ai 3a

3-[5-Acetyl-1-(5- chloro-thiophen-2- ylmethyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.17 (1) 397.03 6aj 3f

1-[3-(3-Chloro- phenyl)-1-(5-chloro- thiophen-2- ylmethyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.25 (1) 406.02 6ak3z

1-[3-(5-Chloro- thiophen-2-yl)-1- (2,4-difluoro- benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.31 (4) 408.01 6al3aa

1-[1-(2,4-Difluoro- benzyl)-3-thiophen- 3-yl-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.21 (4) 374.06 6am 3d

4-[5-Acetyl-3-(3- trifluoromethyl- phenyl)-4,5,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-1- ylmethyl]- benzonitrile 4.52 (2) 425.29 6an3a

3-{5-Acetyl-1-[1-(4- fluoro-phenyl)- ethyl]-4,5,6,7- tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl}- benzonitrile 1.29 (4) 389.2 6ao 3b

1-[1-[Cyclopropyl- (4-fluoro-phenyl)- methyl]-3-(4-fluoro-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone4.55 (2) 408.34 6ap 3e

1-[1-(2,4-Difluoro- benzyl)-3-(3- trifluoromethoxy- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.23 (4) 452.13 6aq3b

1-[1-(2,6-Difluoro- benzyl)-3-(4-fluoro- phenyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.31 (12) 386.03 6ar 3b

1-{3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl}- ethanone 3.65 (8) 382.25 6as3b

1-[3-(4-Fluoro- phenyl)-1-(4- trifluoromethyl- benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.5 (12) 418.11 6at3h

1-[1-(2,4-Difluoro- benzyl)-3-(3- methoxy-phenyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.61 (7) 398.13 6av 3b

1-[3-(4-Fluoro- phenyl)-1-(3- trifluoromethyl- benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.49 (12) 418.02 6aw3e

1-[1-[1-(4-Fluoro- phenyl)-ethyl]-3-(3- trifluoromethoxy-phenyl)-1,4,6,7- tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone1.25 (4) 447.74 6ax 3i

1-[1-(2,4-Difluoro- benzyl)-3-(4-fluoro- 3-methoxy-phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.26 (4)416.22 6ay 3a

3-[5-Acetyl-1-(2,5- difluoro-benzyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.13 (1) 393.13 6az 3q

1-[1-(2,4-Difluoro- benzyl)-3-m-tolyl- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 1.16 (1) 382.3 6ba 3f

1-[3-(3-Chloro- phenyl)-1-(4-fluoro- 2-methyl-benzyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.24 (1)398.12 6bb 3q

1-[1-(2-Fluoro- benzyl)-3-m-tolyl- 1,4,6,7-tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- ethanone 1.26 (4) 364.18 6bc 3d

1-[1-(2-Methoxy- benzyl)-3-(3- trifluoromethyl- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 4.73 (2) 430.32 6bd3f

1-[3-(3-Chloro- phenyl)-1-(3- methoxy-benzyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.19 (1) 396.08 6be 3b

(+)-1-{3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl}- ethanone 4.79 (11) 382.23 6bf3b

(−)-1-{3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl}- ethanone 4.79 (11) 382.23 6bg3b

1-[1-(4-Chloro-3- fluoro-benzyl)-3-(4- fluoro-phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 2.47 (12)402.00 6bh 3g

1-[1-(2,4-Difluoro- benzyl)-3-(2-fluoro- 5-methoxy-phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.13 (4)416.12 6bi 3j

5-[5-Acetyl-1-(2,4- difluoro-benzyl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl]-2- fluoro-benzonitrile 1.26 (4) 411.196bj 3k

1-[1-(2,4-Difluoro- benzyl)-3-(3-fluoro- phenyl)-1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridin-5-yl]- ethanone 3.45 (13) 386.18 6bk 3l

1-[1-(2,4-Difluoro- benzyl)-3-(4- trifluoromethyl- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.2 (1) 435.88 6bl3b

1-[1-[1-(4-Chloro- phenyl)-propyl]-3- (4-fluoro-phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone, enantiomer1 3.81 (8) 412.14 6bm 3b

1-[1-[1-(4-Chloro- phenyl)-propyl]-3- (4-fluoro-phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone, enantiomer2 3.81 (8) 412.14 6bn 3d

1-[1-(2-Fluoro-4- methyl-benzyl)-3- (3-trifluoromethyl- phenyl)-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl]- ethanone 1.35 (4) 432.13

1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,trifluoroacetate salt (7a)

According to Scheme 4:

To a solution of 1 N lithium hexamethyldisilazide in dry tetrahydrofuran(4.69 ml, 4.69 mmol) at −78° C. was added a solution ofN-tert-butoxycarbonyl-4-piperidone (1.0 g, 4.69 mmol) in dry diethylether (9 ml) dropwise and the mixture was stirred at −78° C. for 30 min.A solution of 4-fluorobenzoyl chloride (743 mg, 4.69 mmol) in drydiethyl ether was added. The mixture was allowed to warm to 25° C.overnight. Water was added, the solution was extracted 3 times withCH₂Cl₂, the combined organic layers were washed once with brine, driedover Na₂SO₄, filtrated and the solution was evaporated to dryness,redissolved in ethanol (25 ml) and tetrahydrofuran (11 ml),(2,4-Difluoro-benzyl)-hydrazine (731 mg, 4.62 mmol) was added and themixture was stirred for 10 min at 25° C. The mixture was poured on 1Naqueous NaOH, extracted 3 times with ethyl acetate, the combined organiclayers were washed with brine, dried over Na₂SO₄, filtrated and thesolution was evaporated to dryness. The residue was dissolved in 4NHCl/dioxane (3 ml, 12 mmol) and stirred for 2 days. Solvents wereevaporated and the crude product was purified by reverse phase HPLC(CH₃CN/water gradient with 0.1% trifluoroacetic acid) to give 257 mg of1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,trifluoroacetate salt (7a).

R_(t)=1.05 min (LC-method 4). Detected mass: 358.24 [M+H₊]

1-Benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;hydrochloride (7b)

According to Scheme 5:

A mixture of1-[1-Benzyl-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(6e) (6.9 g, 20 mmol), ethanol (73 ml) and 10N aqueous HCl (137 ml) wasstirred at 80° C. for 2 h and then overnight at room temperature. Themixture was concentrated in vacuo and the product was filtrated off andwashed with a small amount of cold water to give 4.87 g of1-Benzyl-3-(4-fluoro-phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine;hydrochloride (7b).

R_(t)=1.80 min (LC-method 12). Detected mass: 308.17 [M+H₊]

The examples in the following table were obtained according to Scheme 5by following a similar reaction as used for synthesis of (7b). Reactionconditions varied slightly by reaction time (2 h-3 days), concentrationof the aqueous HCl (2-10M) and work-up procedure (sometimes afterevaporation of solvents the residue was purified by reverse phase HPLC(CH₃CN/water gradient with 0.1% trifluoroacetic acid). The free aminewas easily obtained by adding aqueous NaHCO3 and extracting with 3 timesCH₂Cl₂, combining organic layers, drying over Na₂SO₄, filtrating off andevaporating solvents of the filtrate to dryness.

R_(t)/[min] (LC- Comp. Method) No. SC Product Chemical Name [M + H]⁺ 7c6a

3-[1-(2,4-Difluoro- benzyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3-c]pyridin-3-yl]- benzonitrile 0.96 (4) 351.33 7d 6f

1-(2,4-Difluoro- benzyl)-3-(4-fluoro- phenyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3- c]pyridine 1.07 (4) 344.19 7e 6be

3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridine (enantiomer 1) 2.01 (3) 340.1 7f6bf

3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridine (enantiomer 2) 2.01 (3) 340.11

3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-oxetane-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8a)

According to Scheme 6, Method A:

To a 10° C. cold solution of3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile,trifluoroacetate (7c) (0.055 g, 0.118 mmol) in N,N-dimethylformamide (2ml) was added triethylamine (18 μl, 0.13 mmol), 1-hydroxybenzotriazole(17 mg, 0.124 mmol), 3-methyl-3-oxetane carboxylic acid (13.8 mg) andfinally 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24mg, 0.124 mmol). The mixture was allowed to warm to 25° C. and stirredfor 16 h and purified by reverse phase HPLC (CH3CN/water gradient with0.1% trifluoroacetic acid) to give 38 mg of3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-oxetane-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8a).

R_(t)=1.23 min (LC-method 4). Detected mass: 449.27 [M+H₊]

3-[1-(2,4-Difluoro-benzyl)-5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8b)

According to Scheme 6, Method B:

A mixture of3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(7c) (0.057 g, 0.163 mmol), K₂CO₃ (45 mg, 0.327 mmol) and isobutyrylchloride (21 mg, 0.196 mmol) in dry CH₃CN (1.5 ml) was stirred at 60° C.for 1 h. Water was added, the solution was extracted 3 times withCH₂Cl₂, the combined organic layers were washed once with brine, driedover Na₂SO₄, filtrated and the residue was purified by reverse phaseHPLC (CH₃CN/water gradient with 0.1% trifluoroacetic acid) to give 48 mgof3-[1-(2,4-Difluoro-benzyl)-5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8b).

R_(t)=1.18 min (LC-method 1). Detected mass: 421.29 [M+H₊]

3-[5-Cyclopropanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8c)

According to Scheme 6, Method C:

To a 0° C. cold mixture of3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile,hydrochloride salt (7c) (0.050 g, 0.129 mmol), NaHCO₃ (44 mg, 0.517mmol), water (2 ml) and ethyl acetate (2 ml) was addedcyclopropanecarbonyl chloride (13.5 mg, 0.129 mmol) and the mixture wasstirred at 25° C. for 16 h. Water was added, the solution was extracted2 times with ethyl acetate, the combined organic layers were washed oncewith brine, dried over MgSO4, filtrated and purified by reverse phaseHPLC (CH₃CN/water gradient with 0.1% trifluoroacetic acid) to give 21 mgof3-[5-Cyclopropanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8c).

R_(t)=4.14 min (LC-method 13). Detected mass: 419.18 [M+H₊]

3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8d)

According to Scheme 6, Method D:

To a 0° C. cold mixture of3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(7c) (0.4 g, 1.142 mmol) and 2-tert-butoxyacetic acid (196 mg, 1.485mmol) was added N,N-diisopropylethylamine (0.59 g, 4.57 mmol) and TOTU(O-(Cyano(ethoxycarbonyl)methylenamino)-1,1,3,3-tetramethyluroniumtetrafluoroborate, 562 mg, 1.71 mmol) and the mixture was stirred at 25°C. for 1 h. The crude product was purified by reverse phase HPLC(CH₃CN/water gradient with 0.1% trifluoroacetic acid) to give 120 mg of3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8d).

R_(t)=1.34 min (LC-method 4). Detected mass: 465.3 [M+H₊]

3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8w)

According to Scheme 6, Method E:

A mixture of3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(7c) (0.04 g, 0.114 mmol), 3-Methyl-3H-imidazole-4-carbonyl chloride(0.083 g, 0.457 mmol) and triethylamine (138 mg, 1.37 mmol) in CH₂Cl₂was stirred at 25° C. for 16 h. The crude product was purified byreverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid)to give 43 mg of3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8w).

R_(t)=3.53 min (LC-method 2). Detected mass: 459.24 [M+H₊]

1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(8z)

According to Scheme 6, Method F:

A mixture of1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(7a) (0.53 g, 1.35 mmol), acetic anhydride (5.5 ml) and pyridine (5.5ml) was stirred at 25° C. for 16 h. The mixture was poured on 50 mlwater, extracted with 150 ml ethyl acetate, the combined organic layerswere washed with 3 times 0.5 N NaOH (50 ml) and once with brine, driedover MgSO₄, filtrated and evaporated to dryness. The crude product wassilica gel chromatography (eluting with heptane/ethyl acetate) to give156 mg of1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(8z).

R_(t)=1.3 min (LC-method 4). Detected mass: 400.22 [M+H₊]

The examples in the following table were obtained according to Scheme 6by following one of the methods described for the synthesis of 8a-8c(Method (A) according to 8a, Method (B) and Method (C) according to 8c).The acylating reagents are obvious to the man skilled in the art andtherefore not mentioned.

R_(t)/[min] (LC- Comp. SC Method) No. (M) Product Chemical Name [M + H]⁺8e 7c (A)

3-[1-(2,4-Difluoro- benzyl)-5-(3- methanesulfonyl- benzoyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 3.93 (13)533.16 8f 7b (C)

[1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-(4- fluoro-phenyl)- methanone 3.49 (8) 430.1 8g 7b (C)

[1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-(4- methoxy-phenyl)- methanone 3.44 (8) 442.13 8h 7b (C)

[1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]- phenyl- methanone 3.45 (8) 412.1 8i 7c (B)

3-[5-Cyclobutane- carbonyl-1-(2,4- difluoro-benzyl)- 4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.2  (1)433.28 8j 7c (B)

3-[5- Cyclopentane- carbonyl-1-(2,4- difluoro-benzyl)- 4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.23 (1)447.23 8k 7c (A)

3-[1-(2,4-Difluoro- benzyl)-5-(4- methanesulfonyl- benzoyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 3.97 (13)533.15 8l 7c (C)

3-[1-(2,4-Difluoro- benzyl)-5-(tetra- hydro-pyran-4- carbonyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.23 (4)463.29 8m 7c (C)

3-[1-(2,4-Difluoro- benzyl)-5- (tetrahydro-furan- 3-carbonyl)- 4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.23 (4)449.25 8n 7c (B)

3-[1-(2,4-Difluoro- benzyl)-5-(2- methoxy-acetyl)- 4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.24 (4)423.18 8o 7c (B)

3-[1-(2,4-Difluoro- benzyl)-5-(2,2- dimethyl- propionyl)- 4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.36 (4)435.31 8p 7c (B)

3-[1-(2,4-Difluoro- benzyl)-5- propionyl-4,5,6,7- tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.28 (4) 407.27 8q 7c (A)

3-[1-(2,4-Difluoro- benzyl)-5-((S)-2- hydroxy- propionyl)- 4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.18 (4)423.25 8r 7b (C)

1-[1-Benzyl-3-(4- fluoro-phenyl)- 1,4,6,7- tetrahydro- pyrazolo[4,3-c]pyridin-5-yl]-2- phenyl-ethanone 3.47 (8) 426.12 8s 7c (C)

3-[5-Butyryl-1- (2,4-difluoro- benzyl)-4,5,6,7- tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.18 (1) 421.28 8t 7c (C)

3-[1-(2,4-Difluoro- benzyl)-5- (pyridine-2- carbonyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 4.07 (13)456.17 8u 7c (A)

3-[1-(2,4-Difluoro- benzyl)-5-(3- fluoro-pyridine-4- carbonyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 4.49 (2)474.19 8v 7c (A)

3-[1-(2,4-Difluoro- benzyl)-5- (pyrimidine-4- carbonyl)-4,5,6,7-tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]- benzonitrile 1.19 (4)457.31 8x 7c (E)

3-[1-(2,4-Difluoro- benzyl)-5-(1- methyl-1H- pyrazole-3-carbonyl)-4,5,6,7- tetrahydro-1H- pyrazolo[4,3- c]pyridin-3-yl]-benzonitrile 4.49 (2) 459.24 8y 7c (B)

3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridine-5- carboxylic acid ethyl ester 1.35 (4) 423.2

3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,enantiomer 1 (9a)

Enantiomer 1 According to Scheme 7:

To a mixture of3-(4-Fluoro-phenyl)-1-[1-(4-fluoro-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(enantiomer 1) (7e) (0.120 g, 0.353 mmol) and triethylamine (0.135 ml,1.06 mmol) in CH₂Cl₂ at 0° C. was added methanesulfonyl chloride (49 mg,0.424 mmol) and the mixture was stirred at 25° C. for 16 h. The crudeproduct was purified by reverse phase HPLC (CH₃CN/water gradient with0.1% trifluoroacetic acid) to give 96 mg of3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(9a).

R_(t)=3.58 min (LC-method 8). Detected mass: 418.09 [M+H₊]

3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,enantiomer 2 (9b)

Enantiomer 2

3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,enantiomer 2 (9b) was obtained starting from3-(4-Fluoro-phenyl)-1-[1-(4-fluoro-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine(enantiomer 2) (7f) by following a similar reaction as used forsynthesis of (9a).

R_(t)=3.58 min (LC-method 8). Detected mass: 418.09 [M+H₊]

3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid isopropylamide (11a)

According to Scheme 8:

To a mixture of3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(7c) (0.060 g, 0.171 mmol) and triethylamine (138 mg, 1.37 mmol) at 0°C. was added isopropylisocyanate (17.5 mg, 0.21 mmol) and the mixturewas stirred at room temperature for 16 h. The crude product was purifiedby reverse phase HPLC (CH₃CN/water gradient with 0.1% trifluoroacetic)to give 19 mg of3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid isopropylamide (11a).

R_(t)=1.16 min (LC-method 1). Detected mass: 436.25 [M+H₊]

The examples in the following table were obtained according to Scheme 9by following a similar reaction as used for synthesis of (11a).

R_(t)/[min] (LC- Comp. Method) No. SC Product Chemical Name [M + H]⁺ 11b7e

3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid ethylamide,enantiomer 1 3.45 (8) 411.17 enantiomer 1 11c 7f

3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid ethylamide,enantiomer 2 3.45 (8) 411.16 enantiomer 2 11f 7e

3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridine-5- carboxylic acid tert-butylamide,enantiomer 1 4.15 (13) 439.15 enantiomer 1 11h 7c

3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 1,4,6,7- tetrahydro-pyrazolo[4,3- c]pyridine-5- carboxylic acid ethylamide 1.14 (1) 422.21

3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide (12a)

According to Scheme 9:

To a mixture of3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(7c) (0.060 g, 0.171 mmol) and triethylamine (60 mg, 0.60 mmol) in CH₂C₂at 0° C. was added para-nitrophenylchloroformate (38 mg, 0.188 mmol) andthe mixture was stirred at 0° C. for 45 min. 2 M methylamine intetrahydrofuran (2 ml, 4 mmol) was added and the mixture was stirred for3 days at room temperature. The crude product was purified by reversephase HPLC (CH₃CN/water gradient with 0.1% trifluoroacetic) to give 3.4mg of3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylicacid methylamide (12a).

R_(t)=1.11 min (LC-method 1). Detected mass: 408.15 [M+H₊]

The examples in the following table were obtained according to Scheme 10by following a similar reaction as used for synthesis of (12a), but at areaction temperature of 80° C.

R_(t)/[min] Comp. (Method) No. SC Product Chemical Name [M + H]⁺ 12b 7e

{3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro-pyr- azolo[4,3-c]pyridin- 5-yl}-morpholin-4- yl-methanone,enantiomer 1 3.74 (13) 453.11 enantiomer 1 12c 7e

{3-(4-Fluoro- phenyl)-1-[1-(4- fluoro-phenyl)- ethyl]-1,4,6,7-tetrahydro- pyrazolo[4,3- c]pyridin-5-yl}- ((S)-3-hydroxy-pyrrolidin-1-yl)- methanone, enantiomer 1 3.37 (13) 453.11 enantiomer 112d 7c

3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridine-5- carboxylic acid dimethylamide 1.16 (1) 422.212e 7c

3-(3-Cyano- phenyl)-1-(2,4- difluoro-benzyl)- 1,4,6,7-tetrahydro-pyrazolo[4,3- c]pyridine-5- carboxylic acid (2- hydroxy-ethyl)-methyl-amide 1.34 (14) 452.1

2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile(13a)

According to Scheme 10:

To a solution of Zn(CN)₂ (39 mg, 0.335 mmol) andtetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) in dryN,N-dimethylformamide (0.6 ml) at 150° C. was slowly added a solution of1-[3-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone(6j) (0.15 g, 0.335 mmol) in dry N,N-dimethylformamide (1 ml). Themixture was stirred at 150° C. for 3 h and then at 25° C. for 16 h. Themixture was diluted with methyl-tert-butylether, filtrated over Celite,washed with water, dried over Na₂SO₄, filtrated and evaporated todryness. The residue was suspended in methanol, and the solid wasfiltrated off to give 67 mg of2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile(13a).

R_(t)=1.11 min (LC-method 1). Detected mass: 394.22 [M+H₊]

The examples in the following table were obtained according to Scheme 11by following a similar reaction as described for the synthesis of 13a.Sometimes the products were purified by reverse phase HPLC (CH₃CN/watergradient with 0.1% trifluoroacetic acid).

R_(t)/[min] (LC- Comp Method) No. SC Product Chemical Name [M + H]⁺ 13b6w

6-[5-Acetyl-1-(2,4- difluoro-benzyl)- 4,5,6,7- tetrahydro-1H-pyrazolo[4,3- c]pyridin-3-yl]- pyridine-2- carbonitrile 1.11 (1) 394.22

3-[1-(2,4-Difluoro-benzyl)-5-(2-hydroxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(14a)

A solution of3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(8d) (90 mg, 0.193 mmol) and trifluoroacetic acid (221 mg, 1.94 mmol) inCH₂Cl₂ was stirred at 25° C. for 1 day. Solvents were evaporated and theresidue purified by reverse phase HPLC (CH₃CN/water gradient with 0.1%trifluoroacetic acid) to give 48 mg of3-[1-(2,4-Difluoro-benzyl)-5-(2-hydroxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(14a).

R_(t)=1.19 min (method 4). Detected mass: 409.21 [M+H₊]

The following LC methods were used to analyze the exemplary embodiments:

Following abbreviations are used:

FA: formic acidTFA: trifluoroacetic acidACN: acetonitrile

LC Method 1:

-   Stationary phase: Waters UPLC BEH C18 2,1*50 mm; 1.7μ-   Gradient: H₂O+0.05% FA: ACN+0.035% FA 95:5 (0 min) to 5:95(1.1 min)    to 5:95(1.7 min) to 95:5 (1.9 min) to 95:5 (2 min)-   Flow: 0.9 mL/min, 55° C.

LC Method 2:

-   Stationary phase: Waters XBridge C18 4.6*50 mm; 2.5μ-   Gradient: H₂O+0.1% FA: AcN+0.1% FA 97:3 (0 min) to 40:60 (3.5 min)    to 2:98(4 min) to 2:98(5 min) to 97:3 (5.2 min) to 97:3 (6.5 min);-   Flow: 1.3 mL/min

LC Method 3:

-   Stationary phase: WatersXBridgeC18,4,6*50; 2.5μ-   Gradient: H₂O+0.05% TFA: ACN+0.05% TFA 95:5(0 min) to 95:5(0.2 min)    to 5:95(2.4 min) to 5:95(3.2 min) to 95:5(3.3 min) to 95:5(4.0 min)    Flow: 1.7 mL/min, 40° C.

LC Method 4:

-   Stationary phase: Waters UPLC BEH C18 2,1*50 mm; 1.7μ-   Gradient: H₂O+0.1% FA: ACN+0.08% FA 95:5 (0 min) to 5:95(1.1 min) to    5:95(1.7 min) to 95:5 (1.8 min) to 95:5 (2 min)-   Flow: 0.9 mL/min, 55° C.

LC Method 5:

-   Stationary phase: WatersXBridgeC18,4,6*50, 2.5μ-   Gradient: H₂O+0.05% TFA: ACN+0.05% TFA 95:5(0 min) to 95:5(0.2 min)    to 5:95(2.4 min) to 5:95(3.5 min) to 95:5(3.6 min) to 95:5(4.5 min)-   Flow: 1.7 mL/min, 50° C.

LC Method 6:

-   Stationary phase: WatersXBridgeC18,4,6*50, 2.5μ-   Gradient: H₂O+0.05% TFA: ACN+0.05% TFA 95:5(0 min) to 5:95(2.6 min)    to 5:95(3.0 min) to 95:5(3.1 min), to 95:5(4.0 min)-   Flow: 1.7 mL/min, 40° C.

LC Method 7:

-   Stationary phase: Merck Chromolith FastGrad. RP-18e, 50×2 mm-   Gradient: H₂O+0.05% TFA: ACN+0.05% TFA 98:2(0 min) to 98:2(0.2 min)    to 2:98(2.4 min) to 2:98(3.2 min) to 98:2(3.3 min) to 98:2(4 min)-   Flow: 2 mL/min, 50° C.

LC Method 8:

-   Stationary phase: WatersXBridgeC18,4,6*50,2.5μ-   Gradient: H₂O+0.05% TFA: ACN+0.05% TFA 95:5(0 min) to 95:5(0.3 min)    to 5:95(3.5 min) to 5:95(4 min)-   Flow: 1.3 ml/min, 40° C.

LC Method 9:

-   Stationary phase: Waters UPLC BEH C18 2,1*50 mm; 1.7μ-   Gradient: H2O+0.05% FA: ACN+0.035% FA 98:2 (0 min) to 5:95(2 min) to    5:95(2.6 min) to 95:5 (2.7 min) to 95:5 (3 min)-   Flow: 0.9 ml/min 55°

LC Method 10:

-   Stationary phase: 0.2 μl 110×20 LunaC18, 3μ-   Gradient: 0 min 93% H₂O (0.05% TFA)-1.0 min-95% ACN; 95% ACN to 1.45    min; 7% ACN 1.50 min-   Flow: 1 ml/min 55° C.

LC Method 11:

-   Stationary phase: Waters XBridge C18 4.6*50 mm; 2.5μ-   Gradient: H₂O+0.1% FA: ACN+0.08% FA 97:3 (0 min) to 40:60 (3.5 min)    to 2:98(4 min) to 2:98(5 min) to 97:3 (5.2 min) to 97:3 (6.5 min)-   Flow: 1.3 ml, 45° C.

LC Method 12:

-   Stationary phase: YMC JSphere33*2, 4μ-   Gradient: H₂O+0.05% FA: ACN+0.05% FA 95:5(0 min) to 95:5(0.5 min) to    5:95(3.5 min) to 5:95(4 min)-   Flow: 1.3 ml/min, r.t.

LC Method 13:

-   Stationary phase: YMC-Pack JSphere H80 33*2.-   Gradient: H₂O+0.05% TFA: CH₃OH+0.05% TFA 98:2(1 min) to 5:95(5.0    min) to 5:95(6.25 min)-   Flow: 1.0 ml/min, r.t.

LC Method 14:

-   Stationary phase: YMC-JSphere-ODS-H80 (20×2 1 4μ)-   Gradient: 0 min 96% H₂O (0.05% TFA) to 95% CH₃CN (2.4 min) to 4%    CH₃CN (2.45 min)-   Flow: 1.0 ml/min, 30° C.

LC Method 15:

-   Stationary phase: YMC JSphere33*2,4μ.-   Gradient: (AcN+0.05% TFA): H2O+0.05% TFA; 5:95(0 min) to 5:95(0.5    min) to 95:5(3.5 min) to 95:5(4 min)-   Flow: 1.3 ml/min

Determination of the Activity on the TASK-1 Channel in Xenopus Oocytes

Human TASK-1 channels were expressed in Xenopus oocytes. For thispurpose, oocytes were isolated from Xenopus laevis and defoliculated.Subsequently, TASK-1-encoding RNA synthesized in vitro was injected intooocytes. After two days of TASK-1 protein expression, TASK-1 currentswere measured by two-microelectrode voltage clamp. Data were acquiredand analyzed using a TEC-10cx amplifier (NPI Electronic, Tamm, Germany)connected to an ITC-16 interface (Instrutech Corp., Long Island, USA)and Pulse software (HEKA Elektronik, Lambrecht, Germany). Oocytes wereclamped to −90 mV and TASK-1 mediated currents were measured during 500ms voltage pulses to 40 mV. Oocytes were continuously superfused withND96 buffer containing: NaCl 96 mM, KCl 2 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM,HEPES 5 mM (pH adjusted to 7.4 with NaOH). All experiments wereperformed at room temperature.

Test substances were consecutively added to the bath solution at risingconcentrations. Compound effects were calculated as the percentageinhibition of TASK-1 control current before compound application. IC₅₀values were obtained by fitting the data to the general dose-responseequation.

The following products/compounds were tested in said assay by using therespective form (salt or free base) obtained as in the examplesdescribed above and the following activities were measured (IC50 valuesor inhibition (in %) at 5 μM).

Example Inhibition (%) No. IC50 (μM) at 5 μM 6a 0.095 6ab 76% 6ac 80%6ad 86% 6ae 84% 6af 72% 6ag 75% 6ah 53% 6ai 79% 6aj 76% 6ak 0.27 6al 75%6am 0.114 6an 0.187 6ao 0.258 6ap 0.285 6aq 0.359 6ar 0.552 6as 0.6596at 0.72 6av 0.911 6aw 0.947 6ax 0.975 6ay 86% 6az 89% 6b 0.172 6ba 81%6bb 82% 6bc 70% 6bd <10 6be 0.5 6bf 0.5 6bg 0.398 6bh <10 6bi 1.645 6bj1.16 6bk 1.15 6bl 0.966 6bm 0.251 6bn 81% 6c 0.215 6d 0.422 6f 0.598 6g0.0995 6h 0.19 6i 0.216 6j <10 6k 78% 6m 2.441 6n 0.091 6o <10 6p 88% 6q70% 6r 79% 6s 83% 6t 62% 6u 89% 6v 73% 6w <10 6x 82% 6y 86% 6z 75% 8a0.276 8b 0.019 8c 0.047 8d 75% 8e 1.625 8f 1.28 8g 3.264 8h 2.399 8i0.064 8j 0.722 8k 0.906 8l 0.585 8m 0.89 8n 80% 8o 0.131 8p 0.53 8q0.756 8r 1.138 8s <10 8t 0.246 8u 0.416 8v 0.864 8w 1.149 8x 1.878 8y77% 8z 0.511 9a 0.54 9b 0.611 11a 76% 11b 1.52 11c 1.167 11f 58% 11h 91%12a 0.38 12b 0.511 12c 0.734 12d 74% 12e 65% 13a 0.422 13b 0.462 14a <10

Investigation of the Refractory Period and the Left-Atrial Vulnerabilityin the Pig

The compounds were tested for prolongation of the refractory period andantiarrhythmic activity on the atrium of the anesthetized pig asdescribed in the literature (Knobloch et al. 2002. Naunyn-Schmiedberg'sArch. Pharmacol. 366; 482-487). Here the anti-arrhythmic action relatesto the inhibition of the occurrence of episodes of arrhythmias which areinduced by a prematurely placed extra-stimulus (S2) in the left atrium(=left-atrial vulnerability). The refractory period values are stated inpercent of the basal values 15 minutes after injection. Mean values forthe refractory periods are shown from three rates (150, 200 and250/min). The inhibitory values for the inhibition of episodes ofarrhythmias refer to 3 measurements (3 timepoints) before administrationvs. 3 measurements during the first hour after administration of thecompounds.

The action of3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile(6a) on the refractory period of the left atrium and antiarrhythmicactivity in the anesthetized pig after a bolus administration of 1 mg/kgis shown in table 1. From the results shown in table 1, it is seen thatit was possible to prevent 61% of the induced arrhythmias.

TABLE 1 Mean value % increase in the refractory period 14% % inhibitionof the arrhythmias 61% Number of animals n = 3

1: A compound of the formula I

wherein A=(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl; comprising 1-3 heteroatoms selected from the group N, O and S, wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X═(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising 1-3 heteroatoms selected from the group N, O and S, wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—; R2=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-; R3=H or (C₁-C₄)-alkyl-; R4=H or (C₁-C₄)-alkyl-; or R3 and R4 together form a (C₂-C₃)-alkylene bridge; R5=h, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-, (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C₁-C₆)-alkyl-, aliphatic heterocycle, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and four- to seven-membered aliphatic heterocycles comprising an oxygen atom, and wherein the aliphatic heterocycle are optionally substituted with 1 to 3 substituents independently selected from F, OH, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—; R6=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy or (C₁-C₆)-alkyl-O—, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; and R7=H or (C₁-C₆)-alkyl-; wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine, or a stereoisomer, stereoisomeric mixtures or pharmaceutically acceptable salt thereof, with the proviso if R5 is methyl and R2, R3 and R4 are equal to Hand A is equal to 4-fluoro-phenyl, the residue X is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl, 3,4-dichlorophenyl, and with the proviso if R5 is methyl and R2, R3 and R4 are equal to H and X is a phenyl residue, the residue A is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-ethyloxy-phenyl, 3-trifluoromethyl-phenyl, 2-thiophenyl or 4-methylthiophenyl, and with the proviso if R5 is methyl and R2 is methyl and R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl. 2: The compound according to claim 1, wherein A=phenyl or a five- or six-membered heteroaryl selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl and thiophen-3-yl, wherein phenyl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X=a five- or six-membered heteroaryl, comprising 1-3 heteroatoms selected from the group N, O and S, wherein the heteroaryl group is optionally substituted with 1-3 residues selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—; R2=H, (C₁-C₄)-alkyl- or (C₃-C₆)-cycloalkyl-; R3=H or (C₁-C₂)-alkyl-; R4=H or (C₁-C₂)-alkyl-; or R3 and R4 together form a (C₂-C₃)-alkylene bridge; R5=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-, (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C₁-C₆)-alkyl- or aliphatic heterocycle, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and four- to seven-membered aliphatic heterocycles comprising an oxygen atom, and wherein the aliphatic heterocycle is optionally substituted with 1 to 3 substituents independently selected from the group of F, OH, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—; R6=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-, wherein one hydrogen atom of the alkyl group are optionally replaced by OH or (C₁-C₆)-alkyl-O—, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; and R7=H or (C₁-C₆)-alkyl-; wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine, or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof. 3: The compound according to claim 1, wherein A=phenyl, wherein the phenyl residue is optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X=a five- or six-membered heteroaryl, selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, wherein the heteroaryl group is optionally substituted with 1-3 residues selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1=R5-C(═O)— or (C₁-C₂)-alkyl-SO₂—; R2=H, (C₁-C₂)-alkyl- or cyclopropyl-; R3=H or methyl-; R4=H or methyl-; or R3 and R4 together form an ethylene bridge; R5=H, (C₁-C₄)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₂)-alkyl-O—, (C₁-C₂)-alkyl-S—, (C₁-C₄)-alkyl-O-methyl-, HO—(C₁-C₂)-alkyl-, (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-, phenyl, phenyl-(C₁-C₂)-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C₁-C₄)-alkyl- or aliphatic heterocycle, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, and wherein the aliphatic heterocycle is optionally substituted with 1 or 2 substituents independently selected from the group of F, OH, (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, and wherein the phenyl residue is optionally substituted with 1-3 rests selected independently from F, Cl, Br, CF₃, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—, and wherein the heteroaryl residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and pyrazin-3-yl, and wherein the heteroaryl residues are optionally substituted with 1 or 2 rests selected independently from F, Cl, Br, CF3, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—; R6=H, (C₁-C₄)-alkyl- or cyclopropyl, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy; and R7=H, methyl or ethyl; or a stereoisomeric, stereoisomeric mixture or pharmaceutically acceptable salt thereof. 4: The compound according to claims 1, wherein A=phenyl, wherein the phenyl residue is optionally substituted with 1 or 2 rests selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, and (C₁-C₂)-alkyl-S—; X=a five- or six-membered heteroaryl, selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, wherein these residues are optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—; R1=R5-C(═O)— or (C₁-C₂)-alkyl-SO₂—; R2=H, methyl, ethyl or cyclopropyl; R3 and R4=H, and R5=methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, cyclopropyl or cyclobutyl; or a stereoisomer stereoisomeric mixture or pharmaceutically acceptable salt thereof. 5: The compound according to claim 1, wherein A=a five- or six-membered heteroaryl, comprising 1-3 heteroatoms selected from the group N, O and S, wherein the heteroaryl is substituted with 1-3 residues selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X=phenyl, thiophen-2-yl or thiophen-3-yl, wherein these residues are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—; R2=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-; R3=H or (C₁-C₄)-alkyl-; R4=H or (C₁-C₄)-alkyl-; or R3 and R4 together form a (C₂-C₃)-alkylene bridge; R5=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-, (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C₁-C₆)-alkyl- or aliphatic heterocycle, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and four- to seven-membered aliphatic heterocycles comprising an oxygen atom, and wherein the aliphatic heterocycle is optionally substituted with 1 to 3 substituents selected from the group of F, OH, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₉—; R6=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy or (C₁-C₆)-alkyl-O—, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; R7=H or (C₁-C₆)-alkyl-; wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine, or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof, with the proviso that A is not 4-methylthiophenyl if in compounds of formula I R5 is methyl and R2, R3 and R4 are hydrogen and X is phenyl. 6: The compound according to claim 5, wherein A=2-pyridyl, 3-pyridyl or 4-pyridyl, wherein the pyridyl residues are substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, and (C₁-C₂)-alkyl-S—; X=phenyl, thiophen-2-yl or thiophen-3-yl, wherein these residues are substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—; R1=R5-C(═O)— or (C₁-C₂)-alkyl-SO₂—; R2=H, methyl, ethyl, cyclopropyl; R3 and R4=H; R5=H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl; or R5=cyclopropyl, cyclobutyl, cyclopentyl or (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-; or R5=(C₁-C₂)-alkyl-O—, (C₁-C₂)-alkyl-S—, or OCF₃; or R5=(C₁-C₄)-alkyl-O-methyl or HO—(C₁-C₂)-alkyl-; or R5=phenyl or phenylmethyl-, wherein the phenyl residues are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CF₃, (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN and methyl-SO₂—; or R5=R7R6N—, wherein R6=H, (C₁-C₄)-alkyl- or cyclopropyl, wherein one hydrogen atom of the alkyl group are optionally replaced by hydroxy, methoxy or ethoxy; and R7=H, methyl or ethyl; or R5=heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein the heteroaryl residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and wherein the heteroaryl residues are optionally substituted with 1 or 2 rests selected independently from F, Cl, Br, CF₃, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—; or R5=an aliphatic heterocycle, wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl, oxetanyl tetrahydrofuranyl and tetrahydropyranyl, and wherein the aliphatic heterocycle is optionally substituted with 1 or 2 substituents independently selected from of F, (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof. 7: The compound according to claim 1, wherein A=phenyl, wherein the phenyl residue is optionally substituted with 1-3 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X=phenyl, wherein the phenyl group is optionally substituted with 1, 2 or 3 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S—, (C₁-C₄)-alkyl-O—C(O)— and (C₁-C₄)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—; R2=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-; R3=H or (C₁-C₄)-alkyl-; R4=H or (C₁-C₄)-alkyl-; or R3 and R4 together form a (C₂-C₃)-alkylene bridge; R5=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-, (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C₁-C₆)-alkyl- or aliphatic heterocycle, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and four- to seven-membered aliphatic heterocycles comprising an oxygen atom, and wherein the aliphatic heterocycle is optionally substituted with 1 to 3 substituents selected from the group of F, OH, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—; R6=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced hydroxy or (C₁-C₆)-alkyl-O—, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; R7=H or (C₁-C₆)-alkyl-; wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine, with the proviso if R5 is methyl and R2, R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl, 3,4-dichlorophenyl, and with the proviso if R5 is methyl and R2, R3 and R4 are equal to H and X is a phenyl residue, the residue A is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-ethyloxy-phenyl, or 3-trifluoromethyl-phenyl, and with the proviso if R5 is methyl and R2 is methyl and R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl. 8: The compound according to claim 7, wherein A=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—; X=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—, R1=R5-C(═O)— or methyl-SO₂—; R2=H, (C₁-C₂)-alkyl- or cyclopropyl-; R3=H or methyl-; R4=H or methyl-; or R3 and R4 together form an ethylene bridge; R5=heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein the heteroaryl residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and pyrazin-3-yl, and wherein these residues are optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, CF₃, methyl, ethyl, methoxy, ethoxy, CN and methyl-SO₂—; or R5=H; or R5=cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-; or R5=(C₁-C₂)-alkyl-O— or (C₁-C₂)-alkyl-S—; R5=(C₁-C₄)-alkyl-O-methyl- or HO—(C₁-C₂)-alkyl-; or R5=phenyl or phenylmethyl-, wherein the phenyl residues are optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF₃, (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN and methyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R5=R7R6N—, wherein R6=H, (C₁-C₄)-alkyl- or cyclopropyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy, and R7=H, methyl-, ethyl-; R5=an aliphatic heterocycle, wherein the aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl and pyrrolidinyl, wherein the aliphatic heterocycle is optionally substituted with 1 or 2 substituents selected from the group of F, —OH, (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, wherein one or more hydrogen atoms of the alkyl groups are optionally replaced by fluorine; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof. 9: The compound according to claim 7, wherein A=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—, X=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—, R1=R5-C(═O)—; R2=H, (C₁-C₂)-alkyl- or cyclopropyl-; R3=H or methyl-; R4=H or methyl-; or R3 and R4 together form an ethylene bridge; and R5=(C₂-C₄)-alkyl; or R5=methyl; or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof; with the proviso if R5 is methyl and R2, R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-acetoxyphenyl, 2-chloro-phenyl, 3,4-dichlorophenyl. 10: The compound according to claim 1, wherein A=(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising 1-3 heteroatom selected from the group N, O and S, wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X═(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising 1-3 heteroatoms selected from the group N, O and S, wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—; R2=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-; R3=H (C₁-C₄)-alkyl-; R4=H or (C₁-C₄)-alkyl-; or R3 and R4 together form a (C₂-C₃)-alkylene bridge; R5=heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and wherein the heteroaryl residues are optionally substituted with 1-3 residues selected independently from F, C, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not pyrimidin-4-yl, pyridine-2-yl, i-methyl-pyrazol-3-yl or 1-methyl-imidazol-2-yl; or R5 is methyl, with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 2,4-difluorophenyl residue A is not pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 3-cyanophenyl residue A is not a 4-fluorophenyl residue, and with the proviso if in compounds of formula I R3 is methyl, R2 and R4 are hydrogen and X is a 2,4-difluoro-phenyl residue A is not a 4-fluoro-phenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is phenyl A is not phenyl, 3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-ethyloxy-phenyl, 4-acetoxyphenyl, 4-methyl-thiophenyl, 2-thiophenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and A is 4-fluoro-phenyl X is not phenyl, 2-chloro-phenyl, 3,4-dichloro-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-ethyloxy-phenyl, and with the proviso if R5 is methyl and R2 is methyl, and R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl; or R5 is equal to H, (C₂-C₆)-alkyl, CF₃, CF₂H or CFH₂, wherein one or more hydrogen atoms of the alkyl residue are optionally replaced by fluorine; or R5 is equal to (C₃-C₆)-cycloalkyl or (C₃-C₆)-cycloalkyl-(C₁-C₄)-alkyl-, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not cyclopropyl; or R5 is equal to (C₁-C₄)-alkyl-O— or (C₁-C₄)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is equal to (C₁-C₄)-alkyl-O—(C₃-C₂)-alkyl- or HO—(C₁-C₄)-alkyl-; or R5 is equal to phenyl-(C₁-C₄)-alkyl-, wherein the phenyl residue is optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—, and wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methylsulfonyl-phenyl or 4-methy sulfonyl-phenyl; or R5 is equal to R7R6N—, wherein R6=H, (C₁-C₄)-alkyl- or cyclopropyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy, and R7=H or (C₁-C₂)-alkyl-; or R5 is equal to an aliphatic heterocycle, wherein the aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, and wherein the aliphatic heterocycle may be optionally substituted with 1 or 2 substituents selected from the group of F, OH, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-, and wherein one or more hydrogen atoms of the alkyl groups are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methyl-oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl. 11: The compound according to claim 10, wherein A=phenyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl or thiophen-3-yl, wherein these residues are optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—; X=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—, or pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, wherein these residues are optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, C, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₄)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—; R1=R5-C(═O)- or (C₁-C₂)-alkyl-SO₂—; R2=H, (C₁-C₂)-alkyl- or cyclopropyl-; R3=H or (C₁-C₂)-alkyl-; R4=H or (C₁-C₂)-alkyl-; or R3 and R4 together form an ethylene bridge; R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein the heteroaryl residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and wherein these residues are optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, CF₃, methyl, ethyl, methoxy, ethoxy, CN and methyl-SO₂—, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not pyrimidin-4-yl, pyridine-2-yl, i-methyl-pyrazol-3-yl or 1-methyl-imidazol-2-yl; or wherein R5 is methyl, with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 2,4-difluorophenyl residue A is not pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 3-cyanophenyl residue A is not a 4-fluorophenyl residue, and with the proviso if in compounds of formula I R3 is methyl, R2 and R4 are hydrogen and X is a 2,4-difluoro-phenyl residue A is not a 4-fluoro-phenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is phenyl A is not phenyl, 3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-ethoxy-phenyl, 2-thiophenyl, 4-methylthiophenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and A is 4-fluoro-phenyl X is not 2-chloro-phenyl, 3,4-dichloro-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl or 4-acetoxyphenyl; or R5 is equal to H or (C₂-C₄)-alkyl, CF₃; or R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not cyclopropyl, or R5 is equal to (C₁-C₂)-alkyl-O— or (C₁-C₂)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is equal to (C₁-C₄)-alkyl-O-methyl- or HO—(C₁-C₂)-alkyl-, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is equal to phenyl-(C₁-C₂)-alkyl-, wherein the phenyl residues are optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF₃, (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN and methyl-SO₂—, and wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methylsulfonyl-phenyl or 4-methylsulfonyl-phenyl; or R5 is equal to R7R6N—, wherein R6=H, (C₁-C₄)-alkyl-, cyclopropyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy and R7=H, methyl-, ethyl- or R5 is equal to an aliphatic heterocycle, wherein the aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, pyrrolidinyl, and wherein the aliphatic heterocycle is optionally substituted with 1 or 2 substituents selected from the group of F, OH, (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, and wherein one or more hydrogen atoms of the alkyl groups are optionally replaced by fluorine, or a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methyl-oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl. 12: The compound according to claim 10, wherein A is equal to phenyl, wherein the phenyl residue is optionally substituted with 1, 2 or 3 residues selected independently from F, CL, Br, CN, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and X is equal to phenyl, wherein the phenyl group is optionally substituted with 1, 2 or 3 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O—, (C₁-C₄)-alkyl-S—, (C₁-C₄)-alkyl-O—C(O)— and (C₁-C₄)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, and R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—; R2=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-; R3=H or (C₁-C₄)-alkyl-; R4=H or (C₁-C₄)-alkyl-; or R3 and R4 together form a (C₂-C₃)-alkylene bridge; R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and wherein the heteroaryl residues are optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not pyrimidin-4-yl, pyridine-2-yl, 1-methyl-pyrazol-3-yl or 1-methyl-imidazol-2-yl; or R5 is methyl, with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 2,4-difluorophenyl residue A is not pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 3-cyanophenyl residue A is not a 4-fluorophenyl residue, and with the proviso if in compounds of formula I R3 is methyl, R2 and R4 are hydrogen and X is a 2,4-difluoro-phenyl residue A is not a 4-fluoro-phenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is phenyl A is not phenyl, 3-trifluoromethyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methyl-phenyl, 4-ethyloxy-phenyl, 4-methyl-thiophenyl, 2-thiophenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and A is 4-fluoro-phenyl X is not phenyl, 2-chloro-phenyl, 3,4-dichloro-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-ethyloxy-phenyl, 4-acetoxyphenyl, and with the proviso if R5 is methyl and R2 is methyl, and R3 and R4 are equal to H and A is equal to 4-fluoro-phenyl, the residue X is not phenyl, and or wherein R5 is equal to H, (C₂-C₆)-alkyl, CF₃, CF₂H, CFH₂, wherein one or more hydrogen atoms of the alkyl residue may be replaced by fluorine; or wherein R5 is equal to (C₃-C₆)-cycloalkyl or (C₃-C₆)-cycloalkyl-(C₁-C₄)-alkyl-, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not cyclopropyl, or R5 is equal to (C₁-C₄)-alkyl-O— or (C₁-C₄)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is equal to (C₁-C₄)-alkyl-O—(C₁-C₂)-alkyl-O—(C₁-C₂)-alkyl- or HO—(C₁-C₄)-alkyl-; or R5 is equal to phenyl-(C₁-C₄)-alkyl-, wherein the phenyl residues are optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN, (C₁-C₂)-alkyl-SO₂—, and wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methylsulfonyl-phenyl or 4-methylsulfonyl-phenyl; or R5 is equal to R7R6N—, wherein R6=H, (C₁-C₄)-alkyl- or cyclopropyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy, and R7=H or (C₁-C₂)-alkyl- or R5 is equal to an aliphatic heterocycle, wherein the aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl and pyrrolidinyl, wherein the aliphatic heterocycle is optionally substituted with 1 or 2 substituents selected from the group of F, OH, (C₁-C₄)-alkyl-O— and (C₁-C₄)-alkyl-, and wherein one or more hydrogen atoms of the alkyl groups are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methyl-oxetan-3-yl tetrahydrofuran-3-yl, tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl; R6=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by an OH— or (C₁-C₆)-alkyl-O— residue, and wherein one or more hydrogen atoms of the alkyl group is optionally replaced by fluorine; and R7=H or (C₁-C₆)-alkyl-; wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine. 13: The compound according to claim 12, wherein A=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—; X=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—, R1=R5-C(═O)— or methyl-SO₂—; R2=H, (C₁-C₂)-alkyl- or cyclopropyl-; R3=H or methyl-; R4=H or methyl-; or R3 and R4 together form an ethylene bridge; R5 is equal to a heteroaryl or heteroaryl-(C₁-C₆)-alkyl-, wherein the heteroaryl residues are selected from the group consisting of pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-2-yl and payrazin-3-yl, and wherein these residues are optionally substituted with 1 or 2 residues selected independently from F, Cl, Br, CF₃, methyl, ethyl, methoxy, ethoxy, CN and methyl-SO₂—, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not pyrimidin-4-yl, pyridine-2-yl, 1-methyl-pyrazol-3-yl or 1-methyl-imidazol-2-yl, or R5 is methyl, with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 2,4-difluorophenyl residue A is not pyridine-3-yl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl, 3-cyano-phenyl, 3-methoxy-phenyl, 3-trifluormethoxy-phenyl, 2-fluoro-5-methoxy-phenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and X is a 3-cyanophenyl residue A is not a 4-fluorophenyl residue, and with the proviso if in compounds of formula I R3 is methyl, R2 and R4 are hydrogen and X is a 2,4-difluoro-phenyl residue A is not a 4-fluoro-phenyl, and with the proviso if in compounds of formula I R2, R3 and R4 are hydrogen and A is 4-fluoro-phenyl X is not 2-chloro-phenyl, 3,4-dichloro-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl or 4-acetoxyphenyl; or R5 is equal to H, (C₂-C₄)-alkyl or CF₃; or R5 is equal to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or (C₃-C₆)-cycloalkyl-(C₁-C₂)-alkyl-, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not cyclopropyl; or R5 is equal to (C₁-C₂)-alkyl-O— or (C₁-C₂)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is equal to (C₁-C₄)-alkyl-O-methyl- or HO—(C₁-C₂)-alkyl-, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; or R5 is equal to phenyl or phenyl-(C₁-C₂)-alkyl-, wherein the phenyl residues are optionally substituted with 1-3 residues selected independently from F, Cl, Br, CF₃, (C₁-C₂)-alkyl-, (C₁-C₂)-alkyl-O—, CN and methyl-SO₂-, and wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methylsulfonyl-phenyl, 4-methylsulfonyl-phenyl; or R5 is equal to R7R6N—, wherein R6=H, (C₁-C₄)-alkyl- or cyclopropyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy, methoxy or ethoxy, and R7=H, methyl or ethyl; or R5 is equal to an aliphatic heterocycle, wherein the aliphatic heterocycle is selected from the group of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl and pyrrolidinyl, wherein the aliphatic heterocycle may be optionally substituted with 1 or 2 substituents selected from the group of F, OH, (C₁-C₂)-alkyl-O— and (C₁-C₄)-alkyl-, and wherein one or more hydrogen atoms of the alkyl groups are optionally replaced by fluorine, with the proviso if in compounds of formula I A is a 3-cyanophenyl residue and X a 2,4-difluorophenyl residue R5 is not 3-methyl-oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydropyran-4-yl or 1-methyl-piperidin-4-yl, a stereoisomer, stereoisomeric mixture or pharmaceutically acceptable salt thereof. 14: The compound according to claim 10, wherein A=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, (F₂H, CFH₂, methoxy, ethoxy, OCF₃ and (C₁-C₂)-alkyl-S—; X=phenyl, wherein the phenyl residue is substituted with 1 or 2 residues selected independently from F, Cl, Br, CN, (C₁-C₄)-alkyl-, CF₃, CF₂H, CFH₂, methoxy, ethoxy, OCF₃, (C₁-C₂)-alkyl-S—, (C₁-C₂)-alkyl-O—C(O)— and methyl-SO₂—, R1=R5-C(═O)—; R2=H, (C₁-C₂)-alkyl- or cyclopropyl-; R3=H or methyl-; R4=H or methyl-; or R3 and R4 together form an ethylene bridge; R5 is equal to (C₂-C₄)-alkyl; a stereoisomer, stereoisomeric mixtures or pharmaceutically acceptable salt thereof. 15: The compound according to claim 1 selected from the group consisting of 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid isopropylamide; 3-(4-Fluoro-phenyl)-1-[(S)-1-(4-fluoro-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamide; 3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamide; 3-(4-Fluoro-phenyl)-[(S)-1-(4-fluoro-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxy acid tert butylamide; 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethylamnide; 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methylamide; {3-(4-Fluoro-phenyl)-1-[(S)-1-(4-fluoro-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-morpholin-4-yl-methanone; {3-(4-Fluoro-phenyl)-1-[(S)-1-(4-fluoro-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-((S)-3-hydroxy-pyrrolidin-1-yl)-methanone; 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid dimethylamide; 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid (2-hydroxy-ethyl)-methylamide; 2-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-isonicotinonitrile; 6-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-pyridine-2-carbonitrile; 3-[1-(2,3-Difluoro-benzyl)-5-(2-hydroxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 1-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile 1-[1-(2,4-Difluoro-benzyl)-3-(3-methyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-methoxy-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2-Methyl-thiazol-4-ylmethyl)-3-(3-trifluormethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-Thiazol-2-ylmethyl-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-thiophen-2-yl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(5-Chloro-thiophen-2-ylmethyl)-3-m-tolyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(5-Chloro-thiophen-2-ylmethyl)-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 3-[5-Acetyl-1-(5-chloro-thiophen-2-ylmethyl)-4,5,6,7-tetrahydro-1[-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 1-[3-(3-Chloro-phenyl)-1-(5-chloro-thiophen-2-ylmethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(5-Chloro-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-thiophen-3-yl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 4-[5-Acetyl-3-(3-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-ylmethyl]-benzonitrile; 3-{5-Acetyl-1-[1-(4-fluoro-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl}-benzonitrile; 1-[1-[Cyclopropyl-(4-fluoro-phenyl)-methyl]-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(26-Difluoro-benzyl)-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-{3-(4-Fluoro-phenyl)-1-[1-(4-fluoro-phenyl)-ethyl]-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl}-ethanone; 1-[3-(4-Fluoro-phenyl)-1-(4-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(3-methoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(4-Fluoro-phenyl)-1-(3-trifluoromethyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-[1-(4-Fluoro-phenyl)-ethyl]-3-(3-trifluoromethoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-3-methoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 3-[5-Acetyl-1-(2,5-difluoro-benzyl)-4,5,6,7-tetrahydro-1I H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 1-[1-(2,4-Difluoro-benzyl)-3-m-tolyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-y]-ethanone; 1-[1-(6-Chloro-pyridin-3-ylmethyl)-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(3-Chloro-phenyl)-1-(4-fluoro-2-methyl-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2-Fluoro-benzyl)-3-m-tolyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2-Methoxy-benzyl)-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(3-Chloro-phenyl)-1-(3-methoxy-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(4-Chloro-3-fluoro-benzyl)-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(2-fluoro-5-methoxy-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 5-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-fluoro-benzonitrile; 1-[1-(2,4-Difluoro-benzyl)-3-(3-fluoro-phenyl)-4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-trifluoromethyl-phenyl)-1, 4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-[(R)-1-(4-Chloro-phenyl)-propyl]-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-[(S)-1-(4-Chloro-phenyl)-propyl]-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2-Fluoro-4-methyl-benzyl)-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(4-Chloro-pyridin-3-ylmethyl)-3-(3-trifluoroethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(3-Methyl-pyridin-2-ylmethyl)-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(4-Fluoro-benzyl)-3-(6-trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-trifluoroethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(6-trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(4-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(2-Bromo-pyridin-4-y)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(5-Bromo-pyridin-3-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 3-[11-Acetyl-5-(2,4-difluoro-benzyl)-4,5,11-triaza-tricycio[6.2.1.02,6]undeca-2(6),3-dien-3-yl]-benzonitrile; 1-[5-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-4,5,11-triaza-tricyclo[6.2.1.02,6]undeca-2(6),3-dien-11-yl]-ethanone; 1-[1-(6-Chloro-pyridin-3-ylmethyl)-3-m-tolyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]ethanone; 1-[1-(4-Methoxy-pyridin-2-ylmethyl)-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(4-Chloro-pyridin-3-ylmethyl)-3-m-tolyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(3-Methoxy-pyridin-2-ylmethyl)-3-(3-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(3-Chloro-phenyl)-1-(3-methyl-pyridin-2-ylmethyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-[1-(4-Fluoro-phenyl)-ethyl]-3-(6-trifluoromethyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[-(2,4-Difluoro-benzyl)-3-(6-methyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(6-Bromo-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(4-methyl-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[1-(2,4-Difluoro-benzyl)-3-(6-methoxy-pyridin-2-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 1-[3-(6-Chloro-5-methoxy-pyridin-2-yl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-oxetane-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-isobutyryl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[5-Cyclopropanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-11H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[5-(2-tert-Butoxy-acetyl)-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-fluoro-benzyl)-5-(3-methanesulfonyl-benzoyl)-4,5,6,7-tetrahydro-1-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; [1-Benzyl-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-(4-fluoro-phenyl)-methanone; [1-Benzyl-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-(4-methoxy-phenyl)-methanone; [1-Benzyl-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-phenyl-methanone; 3-[5-Cyclobutanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[5-Cyclopentanecarbonyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1I H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-(4-methanesulfonyl-benzoyl)-4,5,6,7-tetrahydro-11H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-(tetrahydro-pyran-4-carbonyl)-4,5,6,7-tetrahydro-[1I-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-(tetrahydro-furan-3-carbonyl)-4,5,6,7-tetrahydro-11H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[3-(2,4-Difluoro-benzyl)-5-(2-methoxy-acetyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-(2,2-dimethyl-propionyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-propionyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-((S)-2-hydroxy-propionyl)-4,5,6,7-tetrahydro-1-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 1-[1-Benzyl-3-(4-fluoro-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-phenyl-ethanone; 3-[5-Butyryl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-(pyridine-2-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; compound with trifluoro-acetic acid; 3-[1-(2,4-Difluoro-benzyl)-5-(3-fluoro-pyridine-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; compound with trifluoro-acetic acid; 3-[1-(2,4-Difluoro-benzyl)-5-(pyrimidine-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-[1-(2,4-Difluoro-benzyl)-5-(1-methyl-1H-pyrazole-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile; 3-(3-Cyano-phenyl)-1-(2,4-difluoro-benzyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid ethyl ester; 1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone; 3-(4-Fluoro-phenyl)-1-[(R)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 3-(4-Fluoro-phenyl)-1-[(S)-1-(4-fluoro-phenyl)-ethyl]-5-methanesulfonyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; their stereoisomeric and/or their pharmaceutically acceptable salts thereof. 16: A medicament comprising a compound of claim 1 or pharmaceutically acceptable salt thereof. 17: The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of diseases of TASK-1 channel-mediated diseases

wherein A=(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl, comprising 1-3 heteroatoms selected from the group N, O and S, wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; X═(C₆-C₁₀)-aryl or a five- or six-membered heteroaryl comprising 1-3 heteroatoms selected from the group N, O and S, wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CN, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-O—C(O)— and (C₁-C₆)-alkyl-SO₂—, wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R1=R5-C(═O)— or (C₁-C₆)-alkyl-SO₂—; R2=H, (C₁-C₆)-alkyl- or (C₃-C₆)-cycloalkyl-; R3=H or (C₁-C₄)-alkyl-; R4=H or (C₁-C₄)-alkyl-; or R3, R4 together form a (C₂-C₃)-alkylene bridge; R5=(C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, (C₁-C₆)-alkyl-O—, (C₁-C₆)-alkyl-S—, (C₁-C₆)-alkyl-)-(C₁-C₆)-alkyl-, HO—(C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-(C₁-C₆)-alkyl-, (C₆-C₁₀)-aryl-, (C₆-C₁₀)-aryl-(C₁-C₆)-alkyl-, R7R6N—, heteroaryl, heteroaryl-(C₁-C₆)-alkyl- or aliphatic heterocycle, wherein the aliphatic heterocycle is selected from the group of morpholinyl, piperidinyl, pyrrolidinyl and four- to seven-membered aliphatic heterocycles comprising an oxygen atom, and wherein the aliphatic heterocycle is optionally substituted with 1 to 3 substituents selected from the group of F, OH, (C₁-C₆)-alkyl-O— and (C₁-C₆)-alkyl-, and wherein the heteroaryl residues are five- or six-membered ring systems, comprising 1-3 heteroatoms selected from the group N, O and S, and wherein aryl and heteroaryl are optionally substituted with 1-3 rests selected independently from F, Cl, Br, CF₃, (C₁-C₆)-alkyl-, (C₁-C₆)-alkyl-O—, CN and (C₁-C₂)-alkyl-SO₂—, and wherein one or more hydrogen atoms of the alkyl moieties are optionally replaced by fluorine; R6=H, (C₁-C₆)-alkyl-, (C₃-C₆)-cycloalkyl-, wherein one hydrogen atom of the alkyl group is optionally replaced by hydroxy or (C₁-C₆)-alkyl-O— residue, and wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine; R7=H or (C₁-C₆)-alkyl-; wherein one or more hydrogen atoms of the alkyl group are optionally replaced by fluorine. 18: The compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of arrhythmias, atrial trachyarrhythnmias, atrial fibrillation or atrial flutter. 19: The compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of sleep-related respiratory disorders, central and obstructive sleep apneas, upper airway resistance syndrome, Cheyne-Stokes respiration, snoring, disrupted central respiratory drive, sudden child death, postoperative hypoxia and apnea, muscle-related respiratory disorders, respiratory disorders after long-term mechanical ventilation (weaning), respiratory disorders during adaptation in high mountains, acute and for respiratory disorders, chronic lung disorders with hypoxia and hypercapnia, chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome; or as a respiratory stimulant for the treatment or prevention of respiratory depression associated with anesthesia or procedural sedations for small interventions or for diagnostic purposes, as a respiratory stimulant for the treatment or prevention of respiratory depression by opioids in chronic pain treatment particularly in cancer or palliative care or procedural sedations and/or for weaning from longterm mechanical ventilation; or for the treatment or prevention of multiple sclerosis and inflammatory or degenerative disorders of the central nervous system. 20: A medicament comprising a compound of claim 15 or a pharmaceutically acceptable salt thereof. 